1. Clofarabine ODAC Presentation Pediatric Acute Leukemia December 1, 2004 Pediatric Acute Leukemia December 1, 2004

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

3. 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 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

4. 4 Agenda Introduction Steve Weitman, MD, PhD Pediatric Leukemia: Robert Arceci, MD, PhD Need for New Treatment OptionsSidney 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

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

6. 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 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

7. 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

8. 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 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

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

10. 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 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

11. 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 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

12. Clofarabine NDA Steve Weitman, MD, PhD Development Overview Clinical Study Results ILEX Oncology, Inc.

13. 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 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

14. 14 Clofarabine Development Timeline Adult Studies Pediatric Studies Phase I Leukemia Phase I/ II CLO/ ARA-C AML, MDS Phase II AML Phase II AML, ALL, MDS, CML Phase II/ III CLO/ ARA-C AML In Development 19991999 20002000 20012001 20022002 2003200320042004 2005 Phase II AML Phase I Leukemia Phase II ALL COG Phase II CLO/ ARA-C AML, ALL In Development

15. 15 Phase I Pediatric ALL & AML Twenty-five patients Dose levels from 11-70 mg/m 2 /day x 5 MTD 52 mg/m 2 /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 Twenty-five patients Dose levels from 11-70 mg/m 2 /day x 5 MTD 52 mg/m 2 /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

16. 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 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

17. 17 Pivotal Pediatric ALL Number of Unique Prior Agents Number of Agents Patients Chemo Drugs Transplant TBI

18. 18 Pivotal Pediatric AML Number of Unique Prior Agents Number of Agents Patients Chemo Drugs Transplant TBI

19. 20042003200220012000 Post-Induction Regimen L-Asparaginase, Vincristine, Cytarabine Cyclophosphamide, Etoposide, Thioguanine Transplant Prep Regimen TBI, Thiotepa, Fludarabine Peripheral Blood SCT 4 Year Old AML Patient Alive with NED Induction Regimen 3 L-Asparaginase Cytarabine Induction Regimen 4 Gemcitabine, Topotecan Thiotepa, Vinorelbine Induction Regimen 5 Cytarabine Idarubicin Induction Regimen 2 Etoposide, Daunorubicin, Cytarabine, Thioguanine Clofarabine Cycle 1 Clofarabine Cycle 2 Clofarabine Cycle 3 Clofarabine Cycle 4 Clofarabine Cycle 5 Off Study Bone Marrow Transplant Clofarabine Induction Regimen 1 Prednisone, Vincristine, Methotrexate

20. Safety and Efficacy Pediatric Leukemia ALL & AML

21. 21 NDA Efficacy/ Safety Population Efficacy data baseN=84 Integrated safety data base N=113 ALLAML Pivotal Studies 4935

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

23. Pivotal Pediatric ALL Efficacy

24. 24 Pivotal Pediatric ALL Characteristics of Study Group Number of Patients 49 Median Age in Years12 (1 - 20) Median # Prior Regimens3 (2 - 6) Patients Refractory to Most Recent Regimen 30 (61%) Patients with Prior Transplants15 (31%)

25. 25 Pivotal Pediatric ALL IRRP Determined Best Objective Response Number (%)95% CI Overall response (CR+CRp) (N=49) 10 (20%)10 - 34% Patients who achieved at least PR (N=49) 15 (31%)18 - 45% Patients who were refractory to most recent regimen (CR+CRp) (N=30) 5 (17%)6 - 35%

26. 26 Pivotal Pediatric ALL Duration of Remission CR + CRp (N=10) Median 20.2 wks CR + CRp (N=10) Median 20.2 wks CR + CRp + PR (N=15) Median 9.7 wks CR + CRp + PR (N=15) Median 9.7 wks Censored Value

27. 27 Pivotal Pediatric ALL Post-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 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

28. 28 Pivotal Pediatric ALL Overall Survival CR + CRp (N=10) Median 58.6 wks CR + CRp (N=10) Median 58.6 wks CR + CRp + PR (N=15) Median 42 wks CR + CRp + PR (N=15) Median 42 wks All Pts (N=49) Median 11.7 wks All Pts (N=49) Median 11.7 wks Censored Value

29. Pivotal Pediatric AML Efficacy

30. 30 Pivotal Pediatric AML Characteristics of Study Group Number of Patients 35 Median Age in Years12 (2 - 22) Median # Prior Regimens 3 (1 - 5) Patients Refractory to Most Recent Regimen 22 (63%) Patients with Prior Transplants 18 (51%)

31. 31 Pivotal Pediatric AML IRRP Determined Best Objective Response Number (%)95% CI Overall response (CR+CRp) (N=35) 1 (3%)0 - 15% Patients who achieved at least PR (N=35) 9 (26%)12 - 43% Patients who were refractory to most recent regimen (CR+CRp, PR) (N=22) 4 (18%)5 - 40%

32. 32 Pivotal Pediatric AML Duration of Remission CR + CRp + PR (N=9) Median 16.2 wks CR + CRp + PR (N=9) Median 16.2 wks Censored Value

33. 33 Pivotal Pediatric AML Post-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 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

34. 34 Pivotal Pediatric AML Overall Survival CR + CRp + PR (N=9) Median 39 wks CR + CRp + PR (N=9) Median 39 wks All Pts (N=35) Median 21 wks All Pts (N=35) Median 21 wks Censored Value

35. 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 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

36. Integrated Safety Analysis

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

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

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

40. 40 Deaths During Study ALL (N=67) AML (N=46) Disease Progression7 (10%)4 (9%) Non Drug-related AE6 (9%)5 (11%) Drug-related AE3 (4%)1 (2%) Includes deaths within 30 days of last dose of study drug

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

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

43. 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 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

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

45. 45 CR After Single Agents in Childhood ALL Adapted from Holland and Frei Cancer Medicine 1974 De Novo ALL CR 6-Mercaptopurine25% Methotrexate20% Cytarabine30% Multi-drug Resistant ALLCR+CRp Clofarabine20%

46. 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 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

47. 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 Clofarabine is Well Tolerated No overlapping toxicities Clofarabine provides Clinical Benefit In a heterogeneous population No meaningful Alternatives

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

49. 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 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

50. 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 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

51. 51 Commitment to Adult 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 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

52. 52 Overall Risk/ Benefit of Clofarabine in Pediatric 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 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

53. Clofarabine ODAC Presentation Pediatric Acute Leukemia December 1, 2004 Pediatric Acute Leukemia December 1, 2004