Bosentan in Pulmonary Arterial Hypertension-Food and Drug PowerPoint Presentation

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01

Slide 18 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01

Slide 19 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01

Slide 20 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01

Slide 21 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01

Slide 22 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01

Slide 23 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01

Slide 25 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01

Slide 26 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01

Slide 27 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01

Slide 28 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01

Slide 29 -

Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters)

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters)

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200)

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200)

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200)

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462)

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01 Risk Reduction Bosentan Monitoring Guidelines Determination of biochemical tests of liver: Pretreatment Monthly for 6 months Quarterly thereafter Discontinue treatment if: ALT/AST > 5 x ULN Increased ALT/AST is associated with symptoms of liver injury 9116.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01 Risk Reduction Bosentan Monitoring Guidelines Determination of biochemical tests of liver: Pretreatment Monthly for 6 months Quarterly thereafter Discontinue treatment if: ALT/AST > 5 x ULN Increased ALT/AST is associated with symptoms of liver injury 9116.01 9117.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01 Risk Reduction Bosentan Monitoring Guidelines Determination of biochemical tests of liver: Pretreatment Monthly for 6 months Quarterly thereafter Discontinue treatment if: ALT/AST > 5 x ULN Increased ALT/AST is associated with symptoms of liver injury 9116.01 9117.01 Risks vs. Benefits Lewis J Rubin, MD Professor of Medicine Director of Pulmonary and Critical Care Medicine Univ of California, San Diego 9118.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01 Risk Reduction Bosentan Monitoring Guidelines Determination of biochemical tests of liver: Pretreatment Monthly for 6 months Quarterly thereafter Discontinue treatment if: ALT/AST > 5 x ULN Increased ALT/AST is associated with symptoms of liver injury 9116.01 9117.01 Risks vs. Benefits Lewis J Rubin, MD Professor of Medicine Director of Pulmonary and Critical Care Medicine Univ of California, San Diego 9118.01 Benefits of Bosentan Treatment Treatment with oral bosentan is associated with: Improvement in 6-min walk test Improvement in dyspnea score during exercise Improvement in WHO functional class Delay in time to clinical worsening Improvement in hemodynamic parameters Maintenance of treatment effect, with no evidence for tolerance 9123.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01 Risk Reduction Bosentan Monitoring Guidelines Determination of biochemical tests of liver: Pretreatment Monthly for 6 months Quarterly thereafter Discontinue treatment if: ALT/AST > 5 x ULN Increased ALT/AST is associated with symptoms of liver injury 9116.01 9117.01 Risks vs. Benefits Lewis J Rubin, MD Professor of Medicine Director of Pulmonary and Critical Care Medicine Univ of California, San Diego 9118.01 Benefits of Bosentan Treatment Treatment with oral bosentan is associated with: Improvement in 6-min walk test Improvement in dyspnea score during exercise Improvement in WHO functional class Delay in time to clinical worsening Improvement in hemodynamic parameters Maintenance of treatment effect, with no evidence for tolerance 9123.01 Risks with Bosentan Treatment Treatment with bosentan is associated with: Decreases in hemoglobin concentration Increased incidence of elevated liver aminotransferases 9125.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01 Risk Reduction Bosentan Monitoring Guidelines Determination of biochemical tests of liver: Pretreatment Monthly for 6 months Quarterly thereafter Discontinue treatment if: ALT/AST > 5 x ULN Increased ALT/AST is associated with symptoms of liver injury 9116.01 9117.01 Risks vs. Benefits Lewis J Rubin, MD Professor of Medicine Director of Pulmonary and Critical Care Medicine Univ of California, San Diego 9118.01 Benefits of Bosentan Treatment Treatment with oral bosentan is associated with: Improvement in 6-min walk test Improvement in dyspnea score during exercise Improvement in WHO functional class Delay in time to clinical worsening Improvement in hemodynamic parameters Maintenance of treatment effect, with no evidence for tolerance 9123.01 Risks with Bosentan Treatment Treatment with bosentan is associated with: Decreases in hemoglobin concentration Increased incidence of elevated liver aminotransferases 9125.01 Elevated Liver Aminotransferases Have been characterized Have been quantified Incidence Degree of severity Can be monitored within PAH treatment paradigm 9126.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01 Risk Reduction Bosentan Monitoring Guidelines Determination of biochemical tests of liver: Pretreatment Monthly for 6 months Quarterly thereafter Discontinue treatment if: ALT/AST > 5 x ULN Increased ALT/AST is associated with symptoms of liver injury 9116.01 9117.01 Risks vs. Benefits Lewis J Rubin, MD Professor of Medicine Director of Pulmonary and Critical Care Medicine Univ of California, San Diego 9118.01 Benefits of Bosentan Treatment Treatment with oral bosentan is associated with: Improvement in 6-min walk test Improvement in dyspnea score during exercise Improvement in WHO functional class Delay in time to clinical worsening Improvement in hemodynamic parameters Maintenance of treatment effect, with no evidence for tolerance 9123.01 Risks with Bosentan Treatment Treatment with bosentan is associated with: Decreases in hemoglobin concentration Increased incidence of elevated liver aminotransferases 9125.01 Elevated Liver Aminotransferases Have been characterized Have been quantified Incidence Degree of severity Can be monitored within PAH treatment paradigm 9126.01 Risks / Benefits Conclusion Treatment with bosentan produces clinically meaningful benefits that substantially outweigh its characterized risks. Oral bosentan fulfills an unmet medical need in patients with PAH. 9128.01

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Bosentan Therapy for Pulmonary Arterial Hypertension Isaac Kobrin, MD Head of Clinical Development Actelion Pharmaceuticals 9001.01 Advisors PAH Lewis J Rubin, MD University of California San Diego Preclin / tox R Michael McClain, PhD Consultant in Toxicology Clin pharm Malcolm Rowland, PhD University of Manchester Hepatology Willis C Maddrey, MD UT Southwestern Medical Center Hematology Jerry L Spivak, MD Johns Hopkins University 9002.01 Bosentan Therapy for PAH Rationale for ET receptor antagonism Preclinical observations Clinical pharmacology Clinical program: Efficacy in patients with PAH Overall safety and tolerability Specific safety issues Drug-induced liver injury (Dr W Maddrey) Risk / benefit assessment (Dr L Rubin) 9003.01 Belongs to a family of 21-amino acid peptides Synthesized and secreted by endothelial cells Acts via 2 receptors: ETA, vascular smooth muscle cells (SMC) ETB, vascular SMC, endothelial cells, fibroblasts Induces vasoconstriction, fibrosis, hypertrophy and hyperplasia Increases vascular permeability Endothelin-1 (ET-1) 9004.01 Rationale for ET Receptor Antagonism in PAH In patients with PAH: Plasma ET-1 levels are increased, and levels correlate with disease severity Increased ET-1 immuno-reactivity in lung vasculature (plexiform lesions) Blockade of ET-1 activity is expected to prevent its detrimental effects ET receptor antagonists are effective in animal models of pulmonary hypertension 9005.01 Bosentan Specific, low MW, competitive ET-receptor antagonist Inhibits the effects of ET-1 by inhibiting its binding to both ETA and ETB receptors 9006.01 Preclinical Observations Related to PAH Pulmonary hypertension Chronic hypoxia Monocrotaline Pulmonary fibrosis Bleomycin Pulmonary inflammation Sephadex Oleic acid Bosentan was studied in models of: 9007.01 Preclinical Observations Related to PAH The main effects of bosentan included: Decrease in pulmonary artery pressure Decreases in pulmonary vascular hypertrophy and right ventricular hypertrophy Decreases in pulmonary fibrosis and inflammation 9008.01 Preclinical Observations Relevant to Human Safety Teratogenicity Decreased RBC parameters Liver injury 9009a.01 Preclinical Observations Testicular Changes In a 2-year rat study, an increased incidence of slight testicular tubular atrophy was observed Not observed in a 2-year mouse study The overall pattern and findings were not typical of drug-induced testicular toxicity No effect on sperm count, motility or male fertility in rats treated with oral bosentan at doses up to 50 times the recommended human dose 9009b.01 Pharmacokinetic Characteristics Dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses) Absorption: tmax at 3.5 hours No relevant food effect Oral bioavailability: approximately 50% 9010.01 Pharmacokinetic Characteristics Terminal elimination half-life: 5.4 hours Protein binding: 98% (mainly albumin) Steady state reached within 3 - 5 days Age, gender, race, body weight and renal function appear not to have a relevant effect on PK properties 9011.01 Metabolism and Excretion Eliminated mainly by hepatic metabolism and subsequent biliary excretion Metabolic pathways: CYP3A4 and CYP2C9 Ketoconazole, a 3A4 inhibitor, led to a 2-fold increase in bosentan exposure Inhibition of 2C9 is not expected to exert a greater effect than ketoconazole CsA, a nonspecific inhibitor of transporters, markedly increased bosentan exposure 9012.01 Influence on Drug Metabolism In vitro bosentan Does not inhibit CYP1A2, 2C9, 2C19, 2D6 or 3A4 Induces CYP2C9, 2C19 and 3A4 In vivo bosentan Decreases exposure to CYP2C9 and 3A4 substrates by 30-60% (HV) Reduced efficacy of CYP2C9 and 3A4 substrates should be considered 9013a.01 Warfarin DDI: Clinical Relevance AC-052-352 Clinical experience in PAH patients (34 placebo and 59 bosentan patients) No change in warfarin dose (BL vs end of treatment) No change in INR (BL vs end of treatment) No difference in warfarin dose changes during treatment vs placebo 9013b.01 Efficacy in PAH Patients 9014.01 Open-label, long-term AC-052-354 (Ongoing) Bos = 200 Overall N = 245 Placebo-controlled AC-052-351 Pbo = 11, Bos = 21 Open-label, long-term AC-052-353 (Ongoing) Bos = 29 Placebo-controlled AC-052-352 Pbo = 69, Bos = 144 PAH Studies for Efficacy Evaluation 9015.01 Study Designs Placebo-controlled Studies 16 BL Period 1 – Evaluation Period 2 – Follow-up 4 Week 0 12 28 Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid AC-052-351 AC-052-352 62.5 mg bid Bosentan 250 mg bid Screen Placebo Bosentan 125 mg bid Placebo 62.5 mg bid 1º Endpoints (Variable Period 2) (Fixed Period 2 for pts who participated) 9016.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Males or females  12 years old PAH due to PPH or secondary to scleroderma or other connective tissue diseases WHO functional class III - IV Baseline 6-min walk test  150 m and  450/500 m Baseline hemodynamics Mean PAP > 25 mmHg PVR > 240 dyn•sec/cm5 PCWP < 15 mmHg Main Inclusion Criteria 9017.01 Main Exclusion Criteria PAH due to other causes (eg, congenital HD, HIV, cirrhosis, thromboembolic, COPD…) SSc/PAH with mod / severe interstitial fibrosis Systolic BP < 85 mmHg ALT / AST > 3 x ULN Hb / Hct > 30% below the LLN PAH treatment modified within 1 month of screening (excluding anticoagulants) Received epoprostenol within 3 months of screening 9018.01 Bos (n = 144) 21:79 49  16 71  20 77:8:15 55:45 Pbo (n = 11) 0:100 47  14 87  18 82:18:0 82:18 M:F (%) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) 19:81 52  12 86  23 76:14:10 81:19 22:78 47  16 74  18 86:1:13 56:44 Bos (n = 21) Pbo (n = 69) Percent or mean  SD AC-052-351 AC-052-352 Demographics 9019.01 90:10 2.5  2.9 71 23 6 100:0 3.0  2.8 91 9 — WHO class (% III:IV) Time from Diag (yrs) Etiology of PAH (%) PPH SSc/PAH Other 100:0 1.7  1.4 81 19 — 94:6 2.3  4.0 70 20 10 Percent or mean  SD Baseline Characteristics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9020.01 55  16 1014  678 2.4  0.8 9.2  3.9 9.8  5.9 56  11 942  430 2.5  1.0 8.3  3.3 9.9  4.1 54  13 896  425 2.4  0.7 9.3  2.4 9.7  5.6 53  17 880  540 2.4  0.7 9.2  4.1 8.9  5.1 Mean  SD Mean PAP (mmHg) PVR (dyn·sec/cm5) CI (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Baseline Hemodynamics AC-052-351 AC-052-352 Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) 9021.01 82 91 55 9 9 Anti-thrombotics (%) Diuretics Calcium antagonists Cardiac glycosides Oxygen 71 86 52 14 29 73 51 52 19 33 70 54 44 19 29 Main Concomitant Medications for PAH Bos (n = 144) Pbo (n = 11) Bos (n = 21) Pbo (n = 69) AC-052-351 AC-052-352 9022.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Disposition AC-052-352 Placebo n = 69 N = 214 n = 69 n = 63 n = 62 Bos 250 mg bid n = 70 n = 70 n = 67 n = 67 Randomized ITT/Safety 6 w/d 1 w/d To open label (AC-052-354) Bos 125 mg bid n = 75 n = 74 n = 71 n = 71 3 w/d 3 w/d Completed Period 1 9024.01 Primary Endpoint 6-minute walk distance at end of Period 1 Secondary Endpoints Time to clinical worsening Death Hospitalization due to PAH Discontinuation due to worsening PAH Start of epoprostenol Lung transplantation / septostomy Efficacy Parameters 9026.01 Change in Borg dyspnea index Change in WHO functional class Change in pulmonary hemodynamics (mean PAP, PVR, CI, mean RAP) Increase in therapy for PAH (Period 1) Efficacy Parameters 9850.01 Statistical Analyses Primary Endpoint All bosentan vs placebo: ITT population AC-052-351: Student’s t-test AC-052-352: Mann-Whitney U-test Management of patients with no valid assessment at the end of Period 1: Due to worsening PAH or death: walk test = 0 m AC-052-351: 1 placebo pt AC-052-352: 3 placebo, 2 bosentan 125 mg bid pts Due to other reasons: last value carried forward 9027.01 6-minute Walk Test Mean Treatment Effect Treatment difference (meters) 20 20 40 60 80 100 120 0 140 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 75.9 (12.5, 139.2) 34.6 (6.2, 63.1) 54.3 (27.3, 81.4) 44.2 (21.4, 67.0) P = 0.0002 P = 0.0205 (P = 0.0001) (P = 0.0107) 9028.02 Robustness of Results Primary Parameter AC-052-351 Mann-Whitney U-test Per-protocol population First 150 patients Pts w/o Wk-16 endpoint Carry forward Zero substitution Pbo CF, bos zero Pbo exclude, bos zero 0.019 0.021* — 0.041 — — — AC-052-352 (0.0002) 0.0011 0.0063 0.0002 0.0008 0.0054 0.0176 P value * Identical to ITT population 9029.01 -10 0 20 40 60 Change in Walk Distance During Period 1 Placebo (n = 11) Bosentan 125 mg bid (n = 21) -10 0 20 40 60 Change in Walk Distance (m) BL 4 8 16 12 Weeks AC-052-352 AC-052-351 Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125/250 mg bid (n = 144) Placebo (n = 69) 9030.01 Change in Walk Distance by Dose During Period 1 in AC-052-352 Bosentan 250 mg bid (n = 70) Placebo (n = 69) Mean  SEM 62.5 mg bid 125 or 250 mg bid Bosentan 125 mg bid (n = 74) -10 0 20 40 60 BL 4 8 16 12 Weeks Change in Walk Distance (m) 9031.02 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo All patients Gender Males Females Age 12 – 20 yrs 21 – 40 yrs 41 – 60 yrs > 60 yrs Weight < 70 kg  70 kg Race White Other 69 15 54 6 15 33 15 29 40 59 10 144 30 114 7 31 71 35 77 67 111 33 20 20 40 60 80 100 120 0 Treatment difference (meters) … 9032.01 Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) Bos Pbo 20 20 40 60 80 100 120 0 All patients WHO class III IV Etiology PPH SSc/PHT Time from < 421 days  421 days Congenital Yes No 69 65 4 48 14 40 29 2 66 144 130 14 102 33 66 77 11 133 diagnosis heart disease … … 138.5 … 9033.01 Treatment difference (meters) Walk Test in Subpopulations Mean Treatment Effect (AC-052-352) 20 20 40 60 80 100 120 0 Location BL walk test Mean PAP Mean RAP CI US Non-US < 345 m  345 m < 52 mmHg  52 mmHg < 8 mmHg  8 mmHg < 2.3 L/min/m2  2.3 L/min/m2 All patients 69 39 30 27 42 37 32 32 35 31 37 144 79 65 79 65 67 77 66 77 75 69 Bos Pbo 9034.01 Treatment difference (meters) Change in Borg Dyspnea Index Mean Treatment Effect Treatment difference (score) 0 1 2 3 0.5 0.5 1.5 2.5 3.5 Bos Pbo 125 mg bid 21 11 AC-052-351 125 mg bid AC-052-352 74 69 250 mg bid 70 69 125/250 mg bid 144 69 Mean (95% CL) 1.6 (3.1, 0.0) 0.4 (1.1, 0.3) 0.9 (1.6, 0.2) 0.6 (1.2, 0.1) 9035.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 p < 0.01 50 75 100 Bosentan 125/250 mg bid Placebo p < 0.01 0 Time to Clinical Worsening Up to Treatment End AC-052-352 p = 0.03 50 75 100 0 AC-052-351 144 69 142 68 31 10 141 63 138 62 103 48 25 7 13 3 Bosentan 125 mg bid Placebo 21 11 21 11 7 1 21 10 21 8 12 4 6 1 2 1 9036.02 Percent Event-free Weeks 0 4 8 12 16 20 24 28 50 75 100 0 p = 0.01 p < 0.03 Time to Clinical Worsening by Dose Up to Treatment End (AC-052-352) Bosentan 74 70 69 72 70 68 18 13 10 71 70 63 70 68 62 55 48 48 14 11 7 7 6 3 Bos 125 Bos 250 Placebo Placebo 9037.01 Pbo (n = 69) Clinical Worsening* Death Hospitalization for PAH D/C for worsening PAH Receipt of epoprostenol *Patients may fall into >1 category No cases of lung transplantation or septostomy 14 (20.3) 2 (2.9) 9 (13.0) 6 (8.7) 3 (4.3) 9 (6.3) 1 (0.7) 6 (4.2) 5 (3.5) 4 (2.8) Bos (n = 144) Pbo (n = 11) Bos (n = 21) 0 0 0 0 0 3 (27.3) 0 3 (27.3) 3 (27.3) 3 (27.3) AC-052-351 AC-052-352 Incidence of Clinical Worsening To End of Period 2 9038.01 Pbo (n = 69) Improved Treatment effect 95% CL Bos (n = 144) Pbo (n = 11) Bos (n = 21) 43% 9% AC-052-351 AC-052-352 Improvement in WHO Class End of Period 1 42% 30% Treatment effect of both studies combined 14.9% (1.3%, 27.0%) 33.8% 5.6%, 58.0% 11.9% 2.9%, 25.2% 9039.01 Change in WHO Class AC-052-351 and AC-052-352 Worsened 1 class (%) No change Improved 1 class Improved 2 classes Mann-Whitney U-test 0 57 43 0 6 64 30 0 2 56 38 4 Pbo (n = 11) Change from BL to end of Period 1 Bos (n = 21) 18 73 9 0 Pbo (n = 69) Bos (n = 144) P = 0.019 P = 0.042 AC-052-351 AC-052-352 9040.01 12 8 6 4 2 0 2 10 Mean PAP (mmHg) PVR (dyn•sec/cm5) Cardiac Index (L/min/m2) PCWP (mmHg) Mean RAP (mmHg) Mean (95% CL) 6.7 (11.9, 1.5) 415 (608, 221) 1.02 (0.65, 1.39) 3.8 (7.3, 0.3) 6.2 (9.6, 2.7) 600 400 300 200 100 0 100 500 Placebo = 10 Bos 125 mg bid = 20 0.25 0.5 1 1.5 0 Changes in Hemodynamics Change to Week 12 (AC-052-351) Placebo-corrected treatment difference 9041.01 % Pts with  1 increase Treatment effect 95% CL % Pts with  2 increases Treatment effect 95% CL Bosentan (n = 144) Placebo (n = 69) 22.2 11.1 29.0 18.8 Period 1 was 16 weeks Increase in Therapy for PAH AC-052-352 (Period 1) 6.8 19.5, 7.1 7.7 18.1, 4.7 9042.01 Patient Allocation to Periods 1 and 2 AC-052-351 Aug 99 Jan 00 Apr 00 Period 1 (12 weeks) Period 2 (variable) P1 P32 Randomization Primary Endpoint Final Endpoint 9845.01 Patient Disposition AC-052-351 N = 32 n = 9 n = 8 n = 8 n = 21 n = 21 n = 21 Randomized ITT/ Safety Completed Period 1 Completed Period 2 To open label (AC-052-353) 1 w/d 2 w/d Bos 125 mg bid n = 21 Placebo n = 11 9023.01 Patient Allocation to Periods 1 and 2 AC-052-352 July 00 Dec 00 Mar 01 Period 1 (16 weeks) Randomization Primary Endpoint Period 2 (fixed 12 weeks) Sep 00 Final Endpoint P1 P48 P213 9846.01 Disposition of Pts Scheduled for Period 2 AC-052-352 Placebo n = 13 N = 48 n = 11 n = 8 Bos 250 mg bid n = 16 n = 15 n = 12 Randomized Completed Period 2 Entered Period 2 3 w/d 1 w/d Bos 125 mg bid n = 19 n = 18 n = 13 5 w/d 3 w/d 1 w/d 2 w/d 9025.01 Maintenance of Efficacy Walk Test Up to 28 Weeks 50 75 100 0 AC-052-351 Bosentan 125 mg bid n = 21 n = 20 n = 6 25 Weeks AC-052-352 50 75 100 0 25 0 4 8 12 16 20 24 28 Bosentan 125/250 mg bid (n = 35) Placebo (n = 13) Change from Baseline (meters) 9493.01 Mean  SEM Bosentan 62.5 mg bid Bosentan 125 mg bid 1 - 4 weeks Bosentan 250 mg bid Bosentan 62.5 mg bid Assessments Walk test at Week 4 WHO class each 6 months Patients 8 / 11 ex-placebo 21 / 21 ex-bosentan 3/31/01 cut off Open-label Extension AC-052-353 9043.01 Baseline (end of 351) Change to Week 4* 393.8  37.9 22.5  14.3 Mean  SEM in meters Ex-placebo (n = 8) Ex-bosentan (n = 21) 438.9  14.2 3.0  9.2 * Treatment in AC-052-351 still blinded for 26 of 29 patients 6-minute Walk Distance Open-label Extension Study AC-052-353 9044.01 Class I (n) Class II Class III Class IV 0 0 29 0 1 12 15 1 1 11 16 1 Start of AC-052-351 6 months 1 year Open-label bosentan WHO class WHO Functional Class Open-label Extension Study AC-052-353 29 patients entered the open-label study 9045.01 Bosentan 125 and 250 mg bid (vs placebo): Increased exercise capacity Consistent in all subpopulations Improved dyspnea on exercise Improved WHO functional class Efficacy Conclusions 9046.01 Efficacy Conclusions Improved pulmonary hemodynamics: cardiac index, mean PAP, PVR and mean RAP (125 mg bid) Decreased risk of clinical worsening With extended treatment: Clinical benefits maintained; no evidence for tolerance 9047.01 9048.01 Safety and Tolerability 9049.01 Bosentan Therapeutic Studies Safety Database 9050.01 Therapeutic Studies N = 972 PAH N = 252 BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9051.01 CHF N = 447 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) Bosentan Therapeutic Studies Safety Database 9052.01 CHF N = 447 HTN N = 243 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) AC-052-354 250 mg/d OL (n = 200) CHF N = 447 HTN N = 243 SAH N = 30 Therapeutic Studies N = 972 PAH N = 252 BC15064/part I 1000 mg/d OL (n = 7) NC15462 1000 mg/d PC, DB (n = 370) BC15064/part II 2000 mg/d PC, DB (n = 36) NC15018 2000 mg/d PC, DB (n = 34) NC15464B 250 mg/d OL (n = 86) NC15020 100-2000 mg/d PC, DB (n = 243) NN15031 1500 mg/d PC, SB (n = 30) BD14884 2000 mg/d PC, DB (n = 7) AC-052-351 250 mg/d PC, DB (n = 32) ENABLE 250 mg/d PC, DB (n = 1613) AC-052-353 250 mg/d OL (n = 29) AC-052-352 250/500 mg/d PC, DB (n = 213) Bosentan Therapeutic Studies Safety Database AC-052-354 250 mg/d OL (n = 200) 9053.01 Subjects in the Database Pharmacology (23 studies) Therapeutic trials 8 Placebo-controlled 3 Open-label (2 extensions) ENABLE (blinded) 155 288 31 Placebo Bosentan 434 677 91 1 : 1 All 571 965 122 1613 About 1522 bosentan-treated patients Additional 62 PAH patients (ex-placebo) given bosentan in AC-052-354 9054.01 Subjects in the Database 8 Placebo-controlled Studies Indication [n (%)] PAH CHF HTN SAH Treatment Placebo Bos 100 mg/d Bos 250-500 mg/d Bos 1000-1500 mg/d Bos 2000 mg/d (28.8) (51.0) (17.0) (3.1) (100) (25.0) (43.3) (28.7) (3.1) (7.4) (31.6) (45.8) (15.2) Placebo (N = 288) Bosentan (N = 677) 83 147 49 9 288 — — — — 169 293 194 21 — 50 214 310 103 9055.01 Exposure to Bosentan Overall and Placebo-controlled Studies 11 Therapeutic Studies 1200 1000 800 600 400 200 0 Days 0 25 50 75 100 Percent of Patients All bosentan doses (N = 715) Mean (SD): 168  271 d 8 Placebo-controlled Studies Days Percent of Patients 4 weeks 526 (73.6%) 3 months 352 (49.2%) 6 months 141 (19.7%) 1 year 88 (12.3%) 3 years 28 (3.9%) 200 100 0 0 25 50 75 100 All bosentan doses (N = 677) Placebo (N = 288) Mean (SD): 101  61 d Mean (SD): 85  64 d 50 150 9056.01 Gender (% M:F) Age (years) Weight (kg) Race (% W:B:O) US / Non-US (%) Placebo (N = 288) 57:43 57  14 77  15 90:4:7 32:68 61:39 57  13 78  17 89:6:6 28:72 Bosentan (N = 677) Percent or mean  SD Patient Demographics 8 Placebo-controlled studies 9057.01 Flushing (%) Leg edema / edema Abnormal hepatic func Headache Anemia % with  1 AE Placebo (N = 288) 1.7 2.7 2.1 12.8 1.0 76.4 With a placebo-subtracted difference of  2% 6.6 7.4 5.9 15.8 3.4 78.1 Bosentan (N = 677) 4.9 4.6 3.8 3.0 2.4 1.7 Placebo-subtracted Treatment-emergent AEs 8 Placebo-controlled Studies 9058.01 Cardiac failure Dyspnea Aggravated PAH Angina pectoris/ chest pain Syncope Hypotension Postural hypotension Dizziness All were more frequent among placebo-treated than bosentan-treated patients Abdominal pain / nausea / vomiting AEs of Specific Interest 8 Placebo-controlled Studies 9059.01 Increased incidence of worsening HF during 1st month of treatment in CHF patients related to: Starting dose (125 and 250 mg bid) Speed of up-titration (weekly to 500 mg bid) Overall incidence of hospitalization for HF was significantly lower with bosentan vs placebo Placebo Bosentan Worsening Heart Failure Overall incidence 64 (22.2%) 120 (17.7%) 60 (40.8%) 114 (38.9%) PC studies (288/677) CHF studies (147/293) 9060.01 REACH-1 (NC15462) Abnormal hepatic func (%) Leg edema / edema Flushing Nasopharyngitis Hypotension % with  1 AE Placebo (N = 80) 2.5 8.8 5.0 7.5 3.8 93.8 With a placebo-subtracted difference of  2% 8.5 13.9 9.1 10.9 6.7 94.5 Bosentan (N = 165) 6.0 5.2 4.1 3.4 2.9 0.7 Placebo-subtracted Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9061.01 Aggravated PAH Cardiac failure Dyspnea Cough Dizziness  2% more frequent on placebo Abdominal pain Nausea/vomiting Gastritis Influenza Limb pain Most Frequent ( 5%) Treatment-emergent AEs AC-052-351 and AC-052-352 9062.01 Abnormal hepatic func [n (%)] Headache Pts with  1 AE Placebo (N = 288) 2 (0.7) 2 (0.7) 27 (9.4) 28 (4.1) 8 (1.2) 75 (11.1) Bosentan (N = 677) AEs ( 1.0%) Leading to Withdrawal 8 Placebo-controlled Studies 9063.01 Placebo (N = 80) Bosentan (N = 165) Abnormal hepatic func [n (%)] Aggravated PAH Cardiac failure Syncope Pts with  1 AE Occurring in > 1 patient per treatment group 3 (1.8) 2 (1.2) 2 (1.2) 0 9 (5.5) 0 6 (7.5) 1 (1.3) 2 (2.5) 8 (10.0) AEs Leading to Withdrawal AC-052-351 and AC-052-352 9064.01 Cardiac failure [n (%)] Sudden death Cardiac arrest Myocardial infarction Total deaths Placebo (N = 288) 1 (0.3) 5 (1.7) 0 0 15 (5.2) 6 (0.9) 3 (0.4) 3 (0.4) 3 (0.4) 31 (4.6) Bosentan (N = 677) Reasons for Death ( 3 patients) 8 Placebo-controlled Studies 9065.01 Cardiac failure [n (%)] Aggravated PHT Pneumonia Pulmonary hemorrhage Sepsis Total deaths Placebo (N = 80) 0 2 (2.5) 0 0 0 2 (2.5) 2 (1.2) 0 1 (0.6) 1 (0.6) 1 (0.6) 4 (2.4) Bosentan (N = 165) All deaths occurring during the study or within 28 days of treatment end Reasons for Death AC-052-351 and AC-052-352 9066.01 Change from BL Pulse rate (bpm) SBP (mmHg) DBP (mmHg) Incidence SBP < 80 mmHg AE hypotension Bosentan (N = 677) 1.0  1.1 4.2  1.4 3.3  1.0 Bosentan (N = 165) Mean change  SEM or percent Placebo (N = 80) 0.2  0.5 3.1  0.7 3.0  0.4 Placebo (N = 288) 0.3  0.7 2.4  1.0 0.4  0.7 PC Studies AC-052-351 + 352 3.3  1.5 3.8  1.8 0.7  1.2 Vital Signs 2.8% 7.6% 0.8% 6.8% 0 3.8% 0.6% 6.7% 9067.01 Evidence for Rebound? Experience limited to 22 PAH patients 5 pts had treatment discontinued after dose reduction 7 pts had treatment interrupted for 2-14 days 10 pts had open-label treatment discontinued PAH-related adverse experiences 1 pt with aggravated PAH (29 days after d/c) No evidence in hypertensive or CHF patients 9068.01 Outcomes in PAH Patients Started on Epoprostenol Ex-placebo n = 8 5 pts improved 1 death 2 pts worse Concomitant bosentan n = 6 Ex-bosentan n = 8 5 pts improved 2 deaths 1 pt worse 5 pts improved 1 death 9071.01 Overall exposure to bosentan 29 patients: 21 of 21 ex-bosentan 8 of 11 ex-placebo 485  97 days (range 105 – 595 days) 28 patients with  1 year 7 patients with  1.5 years Outcomes: No deaths 1 d/c for worsening PAH (epoprostenol) 4 patients up-titrated to 250 mg bid (after 348 – 548 days of treatment) Long-term Experience Open-label Extension Study AC-052-353 9069.01 Long-term Experience Open-label Extension Study AC-052-354 Overall exposure to bosentan 200 patients: 138 of 144 ex-bosentan 62 of 69 ex-placebo 171  73 days (range 25 – 321 days) 100 patients with  6 months 13 patients with  9 months Outcomes: 2 deaths (pulmonary hemorrhage) 2 d/c for worsening PAH (epoprostenol) 6 d/c for elevated ALT/AST 4 d/c for AE/administrative reasons 9070.01 0 Overall Exposure PAH Patients 90 180 270 40 0 May 31, 2001 cut off 360 540 630 100 60 Days 80 Percent of Patients 20 450 Bosentan > 3 months 191 (81.3%) > 6 months 128 (54.5%) > 9 months 41 (17.4%) >12 months 28 (11.9%) >18 months 12 (5.1%) 137.2 patient-years N = 235 9072.01 0 Survival AC-052-351, AC-052-352 and OL Extensions 0.25 0.5 0.75 85 0 1.0 1.25 1.5 100 90 Years 95 Percent Survivors 235 190 125 40 29 21 10 At risk: 9074.01 No relevant difference between bosentan and placebo in SAEs No relevant changes in ECG parameters or treatment-emergent ECG findings No relevant changes in laboratory tests except: Decreases in RBC parameters Increases in liver enzymes Additional Safety Observations 9075.01 Decreases in Hemoglobin Concentration 9076.01 Preclinical Observations Decreases in Hemoglobin Mild (7–13%) decreases in Hb concentration in rats and dogs No evidence for: Hemolysis or immuno-allergic reaction Bone marrow toxicity Bleeding Evidence for increased plasma volume with hemodilution in rats 9077.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.78 0.77 27.8 7.5 3.1 0 0.14 0.55 29.0 24.4 2.6 2.2 Placebo (N = 269) 0.92 1.32 56.8 32.0 5.6 2.2 Bosentan (N = 618) Incidence of Decreased Hb Conc 8 Placebo-controlled Studies Placebo-subtracted LL = < 11.0 g/dl and >15% decrease from baseline 9078.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 0.96 1.09 34.8 13.8 1.8 1.2 0.01 0.48 30.4 8.9 1.3 1.3 Placebo (N = 79) Placebo-subtracted 0.96 1.57 65.2 22.7 3.0 2.4 Bosentan (N = 161) Incidence of Decreased Hb Conc AC-052-351 and AC-052-352 LL = < 11.0 g/dl and >15% decrease from baseline 9079.01 Hemoglobin Conc (g/dl) Chg to end of treatment Chg to lowest value % of Patients with Decrease of  1.0 g/dl Value < LLN Marked decrease (LL) LL and < 10.0 g/dl 1.02 1.12 35.5 14.6 2.3 1.1 0.41 0.44 14.0 3.2 0 0 HTN (N = 231) PAH (N = 248) 0.91 0.87 36.5 13.5 5.0 0.3 CHF (N = 405) Incidence of Decreased Hb Conc Placebo-corrected Incidence LL = < 11.0 g/dl and >15% decrease from baseline 9080.01 Among PAH Patients with Anemia No evidence for increase in bilirubin No associated decrease in WBCs or platelets No increase in eosinophils above the ULN No premature withdrawal due to anemia Blood transfusions in 4 patients (2.4%) 1 epistaxis, 2 GI bleeding, and 1 anemia All 8 PC studies: 1.8% on bosentan 1.0% on placebo 9081.01 Time to Occurrence Decreases in Hemoglobin 8 0 16 24 32 Weeks Percent of Patients at Risk Marked decrease ( 15% and < 11 g/dl) Marked decrease ( 15% and < 10 g/dl) Decrease of  1 g/dl Bosentan (N = 636) Placebo (N = 271) 20 10 0 20 10 0 0 100 50 8 Placebo-controlled Studies 9082.01 Change in Hb Concentration NC15462 and NC15464B Change from Baseline Hb (g/dl) Bosentan (n = 29) 500 mg bid Placebo (n = 7) BL 3 4 12 26 BL 12 Weeks Weeks Median and 25th and 75th percentiles Bosentan (n = 29) Bosentan (n = 7) 125 mg bid NC15462 (REACH-1) NC15464B (open label) 9083.01 Change in Hb Concentration AC-052-352 BL 4 16 Median and 25th and 75th percentiles 8 12 Weeks Bosentan (n = 120) 125 mg bid Placebo (n = 53) Change from Baseline Hb (g/dl) 9084.01 Unlikely Reasons Decrease in Hemoglobin Hemolysis: No increase in bilirubin No increase in reticulocytes or MCV Bone marrow toxicity: No concomitant marked decreases in WBC or platelet counts Normal bone marrow evaluations (2 cases) Bleeding tendency: No evidence for bleeding in most cases 9085.01 Possible Mechanisms Decrease in Hemoglobin Hemodilution / fluid shift Preclinical evidence for increased plasma volume Compatible with clinical picture Compatible with mechanism of action Vasodilation Decreased capillary permeability Decrease in elevated erythropoetin levels 9086.01 Risk to the patient is small Hb concentration should be evaluated after 1 and 3 months of treatment and quarterly thereafter Cases of marked decrease in Hb concentration should be further evaluated and/or treated, based on clinical judgment Risk Management Decrease in Hemoglobin 9087.01 Increases in Liver Aminotransferases 9088.01 Preclinical Observations Evidence for cholestasis Increase in plasma bile salts and alk phos No evidence for: Reactive or toxic metabolites Immuno-allergic reaction Centrolobular necrosis Mitochondrial toxicity Competitive inhibition of bile salt excretion (Bsep), which can lead to accumulation of bile salts and hepatocellular lysis 9089.01 2000 PAH (%) CHF HTN All — 4.2 10.0 6.9 — 15.8 11.4 14.5 12.7 13.8 6.9 11.2 All 250/500 1000/1500 12.7 — 4.3 10.9 100 — — 2.1 2.1 Bosentan Dose (mg/d) Incidence on placebo was approximately 2% Elevated ALT/AST > 3 x ULN by Dose Safety Database Database 9090.01 8 PAH (N = 165) Others (N = 493) All (N = 658) ENABLE (N  807)* 4.2 3.9 4.0 2.8 1.8 3.2 2.9 2.0 12.7 10.8 11.2 8.6 >3 - < 5 5 - < 8 6.7 3.7 4.4 3.8 * Percentages assume all events occur on bosentan, as data are still blinded ALT / AST (x ULN) Severity of Elevated ALT/AST Safety Database All Database (%) 9091.01 Bosentan (mg bid) 125 (N = 95) AE abn hepatic func [n (%)] ALT/AST > 3 x ULN ALT/AST > 8 x ULN Transient cases At target dose With dose reduction Discontinued 10 (14.3) 10 (14.3) 5 (7.1) 4 2 2 3 4 (4.2) 11 (11.6) 2 (2.1) 8 7 1 0 250 (N = 70) Elevated Aminotransferases AC-052-351 and AC-052-352 9092.01 Time Course Elevated Aminotransferases Gradual over several weeks Normalized or reduced to < 2 x ULN during continued treatment (transient) 70% (8/11) with bosentan 125 mg bid (PAH) 40% (4/10) with bosentan 250 mg bid (PAH) 16% (6/38) with bosentan 500 mg bid (CHF) Complete resolution after treatment cessation 9093.01 Safety database AC-052-354 ENABLE 3 – 64 18 – 56 10 – 44 Range (days) 33 6 23 Number of cases 26  13 32  13 23  10 Mean  SD (days) Time following treatment end depended on time of evaluation 97% of elevations were resolved within 8 weeks Time to Resolution ALT/AST Returned to Baseline or < 2 x ULN 9094.01 Predisposing Factors Incidence of Elevated ALT/AST > 3 x ULN ALT/AST > 3 x ULN No effect of age or gender With Factor W/o Factor Predisposing factor ALT/AST > ULN at BL (n = 133, 521) Alk phos > ULN at BL (n = 83, 572) Concomitant glibenclamide (n = 31, 213) 10.0% 11.4% 13.3% 16.5% 10.8% 27.5% 9095.01 Time to First Occurrence Elevated Liver Aminotransferases Percent of Patients at Risk Bosentan Placebo 40 20 0 0 40 20 8 Placebo-controlled Studies AC-052-352 Bosentan Placebo 8 0 16 24 32 Weeks (N = 144) (N = 68) (N = 658) (N = 280) 9096.01 0 Time to First Occurrence Elevated Liver Aminotransferases 12 24 36 48 20 10 0 Bosentan (N  807) 69 cases (8.6%) assuming all on bosentan 60 72 84 96 40 30 Week ENABLE Percent of Patients at Risk 9097.01 Associated Symptoms Elevated Liver Aminotransferases Pts with symptoms Nausea/vomiting (n) Abdominal pain Fever Jaundice/bili > 3xULN *Assuming all cases on bosentan 9 / 74 3 2 4 1 PC Studies (N = 677) 2 / 5 2 1 0 1 OL Studies (N = 122) 11 / 69 4 6 2 1 ENABLE (N = 807*) 9098.01 Type of Liver Injury Council for Intl Org of Medical Science Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) Type of Injury Ratio = * The ULN, respectively ALT / 30 U/L* Alk Phos / 95 U/L* 9099.01 Type of Liver Injury Council for Intl Org of Medical Science Total number (%) of cases Cholestatic (ratio  2) Hepatocellular (ratio  5) Mixed (ratio >2, < 5) 67 (100) 3 (4.5) 25 (37.3) 39 (58.2) ENABLE (N = 807†) 74 (100) 7 (9.5) 34 (45.9) 33 (44.6) PC Studies (N = 658) Type of Injury * The ULN, respectively † Assuming all cases are on bosentan ALT / 30 U/L* Alk Phos / 95 U/L* Ratio = 9100.01 Mechanism Elevated Aminotransferases Not yet fully elucidated Competitive inhibition of bile salt excretion may be a contributory factor No evidence for immuno-allergic reaction During treatment At reintroduction 9101.01 Risk Assessment Hyman Zimmerman’s Suggestions Increased risk of acute liver failure in patients with predominantly hepatocellular disease: ALT/AST > 3 x ULN Clinical jaundice (bilirubin > 3 x ULN) May be associated with small changes in alkaline phosphatase Estimated that 10% of patients who have drug- induced liver injury will develop acute liver failure 9102.01 Mean  SD (yrs) (Range) Pts (%) treated > 3 months > 6 months > 9 months >12 months >18 months >24 months PAH Studies (N = 235) 0.58  0.37 (0.07 – 1.71) 0.87  1.16 (0 – 4.11) 183 (68.5) 95 (35.6) 71 (26.6) 61 (22.8) 49 (18.4) 39 (14.6) NC15462 NC15464B (N = 267) 1.13  0.48 (0 – 1.93) 1483 (91.9) 1386 (85.9) 1316 (81.6) 1079 (66.9) 412 (25.5) — ENABLE* (N = 1613) Long-term Exposure to Bosentan 191 (81.3) 128 (54.5) 41 (17.4) 28 (11.9) 12 (5.1) — * Treatment still blinded; about half on bosentan 9512.01 Risk Assessment with Bosentan Among the 1522 bosentan-treated patients: No cases of acute liver failure 3 pts have had ALT/AST and bilirubin > 3 x ULN and also had alk phosphatase 2-3 x ULN 1 in AC-052-352 (250 mg bid) 1 in NC15464B (open-label 125 mg bid) 1 in ENABLE (blinded treatment) All 3 had complete resolution within 24-64 days of treatment cessation (based on evaluation date) 9103.01 Clinical Picture Elevated Aminotransferases Overall incidence of 11.2% Incidence and severity are dose related Onset mainly during the first 16 weeks of treatment Gradual increase over several weeks Transient in 50% of cases 9104.01 Clinical Picture Elevated Aminotransferases Typically asymptomatic Associated with elevated alkaline phosphatase in about 50% of cases Infrequently associated with elevated bilirubin (> 3 x ULN) Rapid and complete resolution with treatment cessation No evidence for continued liver injury 9105.01 Is the Risk of Increased Liver Aminotransferases Manageable? PAH patients are very compliant and have a close relationship with their physicians Recommendations: Monthly monitoring for first 6 months and quarterly thereafter Monitoring can be incorporated into the routine management of these patients (INR/chemistries) 9106.01 Guidelines for treatment modification Reduce or interrupt treatment: ALT/AST > 3 and < 5 x ULN Stop treatment: ALT/AST > 5 x ULN, or increase in ALT/AST associated with symptoms of liver injury, or bilirubin > 3 x ULN Education of physicians, nurses, pharmacists Information to patients, directly via drug distribution and through patient organizations Is the Risk of Increased Liver Aminotransferases Manageable? 9107.01 Starting dose: bosentan 62.5 mg bid (4 weeks) Target dose: No dose adjustment needed for most subgroups Not recommended for: Pts with moderate to severe liver impairment Pts with ALT/AST > 3 x ULN at baseline Pts on glibenclamide or cyclosporin A Pregnant women Recommended Dosages 9108.01 bosentan 125 mg bid Treatment with bosentan is associated with: Improvement in all clinical and hemodynamic efficacy measures Reduction in risk of clinical worsening Good tolerability Potential risks related to: Modest decrease in Hb concentration Increase incidence of elevated liver enzymes Both can be managed by appropriate monitoring and education Overall Summary 9109.01 Risk Related to Elevated Liver Aminotransferases Willis C Maddrey, MD Executive VP for Clinical Affairs UT Southwestern Medical Center and Aston Ambulatory Care Ctr 9110.01 Signals of Drug-induced Hepatotoxicity Major: Development of acute liver failure Onset of clinically apparent jaundice Appearance of ascites, encephalopathy, coagulopathy Intermediate: ALT > 8 x ULN ALT > 5 x ULN ALT > 3 x ULN Minor: Any elevation in ALT (< 3 x ULN) in an asymptomatic patient 9111.01 Relevance of Elevated Liver Aminotranferases Inexact correlations with injury Important role of associated signs and symptoms > 3 x ULN equal to inflammation on liver biopsy > 5 x ULN triggers considerably heightened awareness and follow-up (treatment withdrawal should be considered) Drugs associated with liver injury tend to have a signature pattern 9112.01 Drug-induced Hepatocellular Jaundice Zimmerman Observations / Rule In patients with drug-induced hepatoxicity who have elevated aminotransferase levels (> 3 x ULN), clinical jaundice (bilirubin > 3 mg/dl), and a relatively little change in alkaline phosphatase, there is an approximately 10% mortality rate. Drugs studied: Isoniazid ~10% Methyldopa ~10% Tienilic acid ~10% 9114.01 Bosentan-induced Hepatotoxicity Injury – hepatocellular or mixed Incidence of elevated ALT/AST 11.2% with > 3 x ULN 0.6% with > 20 x ULN Onset usually (> 90%) within 16 weeks All elevations resolved upon drug withdrawal (97% within 8 weeks) No cases of acute liver failure 9115.01 Risk Reduction Bosentan Monitoring Guidelines Determination of biochemical tests of liver: Pretreatment Monthly for 6 months Quarterly thereafter Discontinue treatment if: ALT/AST > 5 x ULN Increased ALT/AST is associated with symptoms of liver injury 9116.01 9117.01 Risks vs. Benefits Lewis J Rubin, MD Professor of Medicine Director of Pulmonary and Critical Care Medicine Univ of California, San Diego 9118.01 Benefits of Bosentan Treatment Treatment with oral bosentan is associated with: Improvement in 6-min walk test Improvement in dyspnea score during exercise Improvement in WHO functional class Delay in time to clinical worsening Improvement in hemodynamic parameters Maintenance of treatment effect, with no evidence for tolerance 9123.01 Risks with Bosentan Treatment Treatment with bosentan is associated with: Decreases in hemoglobin concentration Increased incidence of elevated liver aminotransferases 9125.01 Elevated Liver Aminotransferases Have been characterized Have been quantified Incidence Degree of severity Can be monitored within PAH treatment paradigm 9126.01 Risks / Benefits Conclusion Treatment with bosentan produces clinically meaningful benefits that substantially outweigh its characterized risks. Oral bosentan fulfills an unmet medical need in patients with PAH. 9128.01