Clofarabine ODAC Presentation Pediatric Acute Leukemia PowerPoint Presentation

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Clofarabine ODAC Presentation Pediatric Acute Leukemia December 1, 2004

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Clofarabine ODAC Presentation Steve Weitman, MD, PhD Chief Medical Officer ILEX Oncology, Inc.

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3 Clofarabine ODAC Consultants Sima Jeha, MD St. Jude Children’s Research Hospital Ka Wah Chan, MD M.D. Anderson Cancer Center Laurel Steinherz, MD Memorial Sloan-Kettering Cancer Center Robert Arceci, MD, PhD Sidney Kimmel CCC at Johns Hopkins Peter Steinherz, MD Memorial Sloan-Kettering Cancer Center Stephen Sallan, MD Dana-Farber Cancer Institute Varsha Gandhi, PhD M.D. Anderson Cancer Center Eric Sandler, MD Nemours Children’s Clinic Peter Adamson, MD Children’s Hospital of Philadelphia

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4 Agenda Introduction Steve Weitman, MD, PhD Pediatric Leukemia: Robert Arceci, MD, PhD Need for New Treatment Options Sidney Kimmel CCC at Johns Hopkins Clofarabine Pivotal Studies Steve Weitman, MD, PhD Clinician’s Perspective Stephen Sallan, MD Dana-Farber Cancer Institute Clofarabine Development Plan Steve Weitman, MD, PhD

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The Challenge Robert Arceci, MD, PhD Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsDepartments of Oncology and Pediatrics Pediatric Leukemia:Need for New Treatment Options

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6 Treatment of Patients with Pediatric Leukemias Treatments for newly diagnosed patients with ALL & AML use aggressive multi-drug regimens Overall survival for pediatric ALL and AML has improved, but is approaching a plateau 20% ALL and 50% AML have disease recurrence

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7 Common Pediatric Cancers De Novo ALL & AML CNS Source: SEER Pediatric Monograph Assumes: 75% ALL cases cured and 50% AML cases cured Relapsed/ Refractory ALL & AML

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8 Challenges in Pediatric Relapsed & Refractory Leukemias Heterogeneous population Multi-drug resistance is common in leukemia cells, particularly at relapse Dose intensification with combination therapies has resulted in significant co-morbidities and organ dysfunction Transplant is the best curative option but requires disease control and time to identify donor

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9 Survival in Relapsed/ Refractory Pediatric Leukemia Weitman, et. al. J Pediatr Hematol Oncol. 1997;17:197-207 Acute Lymphoid Leukemia Acute Myeloid Leukemia

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10 New Agents Needed for Remission Induction in Relapsed/ Refractory Patients Few agents have been approved for pediatric leukemia Most commonly used agents approved many years ago Methotrexate (1953) 6-Mercaptopurine (1953) Vincristine (1963) Ara-C (1969) Doxorubicin (1974) Development of new pediatric oncology agents has lagged behind adult oncology drug development

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11 Conclusions Relapsed leukemia is the third most common childhood cancer Successful treatment of relapsed and refractory pediatric leukemias remains a major challenge Patients with multi-drug resistant leukemia are refractory to chemotherapy and have accumulated organ toxicities New, well tolerated and effective agents are urgently needed

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Clofarabine NDA Steve Weitman, MD, PhD Development OverviewClinical Study Results ILEX Oncology, Inc.

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13 Clofarabine Development Overview Adult Phase I studies started in 1999 Pediatric Phase I studies started in 2000 Striking activity in heavily pretreated population with acceptable toxicity profile Compelling results in pediatric patients with an unmet medical need Propelled development in pediatrics at a faster rate than adults Increased the request for expanded access due to lack of alternative studies

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14 Clofarabine Development Timeline Adult Studies Pediatric Studies Phase II/ III CLO/ ARA-C AML In Development 1999 2000 2001 2002 2003 2004 2005 COG Phase II CLO/ ARA-C AML, ALL In Development

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15 Phase I Pediatric ALL & AML Twenty-five patients Dose levels from 11-70 mg/m2/day x 5 MTD 52 mg/m2/day IV DLT was reversible increases in bilirubin and skin rash Response CR 5/25 (20%) PR 3/25 (12%) 7 of 25 patients went to transplant Jeha, et. al. Blood. 2004;103:784-789

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16 Pivotal Pediatric ALL & AML Planned Study Design Primary Endpoint is Overall Response Rate (CR+CRp) Fleming 2 stage design - (40% response rate of interest was based on 1 to 2 prior regimens) Current Clinical Practice Population was heavily pretreated, having highly resistant leukemia (up to 6 prior regimens) Patients went to transplant before count recovery The study size was expanded in collaboration with FDA to understand the true response rate

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17 Pivotal Pediatric ALL Number of Unique Prior Agents Number of Agents Patients

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18 Pivotal Pediatric AMLNumber of Unique Prior Agents Number of Agents Patients

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4 Year Old AML Patient

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Safety and EfficacyPediatric Leukemia ALL & AML

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21 NDA Efficacy/ Safety Population Efficacy data base N=84 Integrated safety data base N=113

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22 Pivotal Study Endpoints Key Efficacy Endpoints: Independent Response Review Panel (IRRP) determined response: CR, CRp, PR Duration of remission Post-treatment transplants Survival Safety

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Pivotal Pediatric ALL Efficacy

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24 Pivotal Pediatric ALL Characteristics of Study Group

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25 Pivotal Pediatric ALLIRRP Determined Best Objective Response

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26 Pivotal Pediatric ALLDuration of Remission CR + CRp (N=10) Median 20.2 wks CR + CRp + PR (N=15) Median 9.7 wks

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27 Pivotal Pediatric ALLPost-Clofarabine Transplants 14% of patients went to transplant (7/49) 2 CR, 2 CRp, 2 PR, 1 NE Median time to transplant was 32 days (range 16 - 77) Median number cycles was 2 (range 2 - 3) 5 of 7 patients alive post-transplant

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28 Pivotal Pediatric ALLOverall Survival CR + CRp (N=10) Median 58.6 wks CR + CRp + PR (N=15) Median 42 wks All Pts (N=49) Median 11.7 wks

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Pivotal Pediatric AML Efficacy

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30 Pivotal Pediatric AML Characteristics of Study Group

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31 Pivotal Pediatric AML IRRP Determined Best Objective Response

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32 Pivotal Pediatric AMLDuration of Remission CR + CRp + PR (N=9) Median 16.2 wks

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33 Pivotal Pediatric AMLPost-Clofarabine Transplants 34% of patients went to transplant (12/35) 1 CRp, 6 PR, 3 NE, 2 TF Median time to transplant was 38 days (range 21 - 75) Median number of cycles was 2 (range 1 - 5) 7 of 12 patients alive post-transplant

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34 Pivotal Pediatric AMLOverall Survival CR + CRp + PR (N=9) Median 39 wks All Pts (N=35) Median 21 wks

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35 Pivotal ALL & AML Efficacy Summary Recurrent pediatric acute leukemia is a substantial unmet medical need, especially for patients with AML Impressive response rates with Clofarabine for pediatric patients with ALL and AML that has become cross-resistant to most currently available agents The duration of remission was more than sufficient to allow patients with donors the opportunity to proceed to transplant Long-term survival was observed in patients with ALL and AML who responded to Clofarabine

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Integrated Safety Analysis

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37 All Grade 3 & 4 Adverse Events in > 10% of Pediatric Patients (N=113) Integrated Safety

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38 Drug-Related Grade 3 & 4 Adverse Events in > 5% of Pediatric Patients (N=113) Integrated Safety

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39 All Grade 3 & 4 Hepato-Biliary/ Renal Lab Abnormalities

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40 Deaths During Study Includes deaths within 30 days of last dose of study drug

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41 Integrated Safety Summary Heavily pretreated population Many adverse events were consistent with underlying leukemia Events are not unexpected for a cytotoxic agent Most adverse events were reversible

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Stephen Sallan, MD Clinician’s Perspective Dana-Farber Cancer Institute

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43 Childhood Leukemia ALL 75 - 80% cured with multi-drug chemotherapy AML 40 - 50% are cured Successful treatment of relapsed and refractory pediatric leukemias remains a major challenge

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44 Survival in Pediatric Leukemias Year Five Year Relative Survival Rates Kersey, Blood. 1997; 90(11):4243-4251 ALL AML

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45 CR After Single Agents in Childhood ALL Adapted from Holland and Frei Cancer Medicine 1974

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46 What Impresses Me As A Clinician ALL Clofarabine results 1 in 5 children with multi-drug resistant ALL achieved a CR, affording them a transplant option AML Clofarabine results 1 in 3 children with multi-drug resistant AML went to transplant Transplant is the curative therapeutic option in drug-resistant childhood ALL and AML

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47 What Impresses Me As A Clinician Clofarabine is Well Tolerated No overlapping toxicities Clofarabine provides Clinical Benefit In a heterogeneous population No meaningful Alternatives

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Commitment to Pediatric Clinical Development Steve Weitman, MD, PhD ILEX Oncology, Inc.

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49 Commitment to Pediatric Clinical Development This represents a new paradigm in pediatric drug development The sponsor commits to further develop this drug in children: Continue survival follow-up on pivotal studies Moving to less heavily pretreated ALL and AML patients Proceed to a randomized study in pediatric patients Our commitment includes working closely with the Children’s Oncology Group and CTEP

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50 Commitment to Pediatric Clinical Development Children’s Oncology Group (COG)/ CTEP AML Ara-C/Clofarabine Combination Study First relapsed patients Study chairs: Razzouk and Cooper ALL Cytoxan/Clofarabine and Etoposide/Clofarabine Combination Study Second relapsed patients Study chair: Hijiya

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51 Commitment toAdult Clinical Development Program Objectives Focused on AML and MDS Combination studies with Ara-C Interest in elderly population of patients Adult Leukemia Studies CLO-141 Phase I/II Combination Ara-C/Clofarabine in AML Randomized studies planned Phase II/III Ara-C/Clofarabine in elderly patients with De Novo AML Phase II/III Ara-C/Clofarabine in non-elderly adult patients with relapsed AML Adult Development Discussion with FDA Ongoing

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52 Overall Risk/ Benefit of Clofarabine inPediatric Leukemia Acceptable safety profile in this heavily pre-treated patient population Impressive benefits Provided meaningful clinical response and cytoreduction (CR, CRp, and PR) Overall, 23% of patients proceeded to transplant (19/84) 14% of patients with ALL 34% of patients with AML Patients alive at data cutoff - ALL 22%, AML 26% (Median follow-up 29 weeks) Meets an urgent unmet medical need in highly resistant pediatric leukemia

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Clofarabine ODAC Presentation Pediatric Acute Leukemia December 1, 2004