Zarnestra NDA 21824

1. ZarnestraNDA 21824 Qin Ryan MD, PhD DODP/CDER/FDA

2. Outline • Regulatory Background • Clinical Overview and Proposed Indication • CTEP-20 Design • CTEP-20 Efficacy • CTEP-20 Safety • Summary

3. Regulatory Background

4. Regulatory Background • In oncology, clinical benefit (CB) has been defined as a longer life, a better life or an effect on an established surrogate for either • In acute leukemias, durable complete remission (CR) has been considered evidence of benefit • In some cases where leukemia CR’s were of uncertain duration, CR was considered a surrogate reasonably likely to predict CB

5. Drug Approvals for AML

6. Clinical Overview

7. Induction Therapy for AML • Untreated AML progresses rapidly to death • Standard Rx in Adults < 60: • 60-75% CR • < 20% treatment related death • DFS 20-50% • 30-40% survive > 3 years • Factors affecting outcome: PS, organ function, co-morbidity, age, karyotype

8. Induction Chemotherapy for Elderly Patients with AML Menzin et al., Arch Intern Med 2002, 162: 1597.

9. Survival in Elderly Patients with AML Menzin et al., Arch Intern Med 2002, 162: 1597.

10. Higher mortality and morbidity seen in elderly patients with poor-risk AML receiving standard chemotherapy Elderly Patients with Poor-Risk AML

11. Clinical Program

12. Zarnestra • Farnesyl transferase inhibitor • 100 mg Tablets • 600 mg twice daily PO for 21 days, followed by a rest period of 7 - 42 days

13. Proposed Indication • Treatment of elderly patients with newly diagnosed poor-risk acute myeloid leukemia.

14. Zarnestra NDA: AML Trials * Conducted by NCI, CTEP as part of a Cooperative Research and Development Agreement with J&J

15. CTEP-20 Design

16. CTEP-20 Design • Open-label, single-arm, multicenter • Population • Original: untreated poor-risk hematological malignancies • 6th amendment (after 110 enrollments): untreated elderly poor-risk AML • Age > 75 • Age 65-74 AML with prior MDS

17. CTEP-20 Design • Primary objective • Original: RR (CR+PR) • 6th amendment: complete response (CR) rate in untreated elderly poor-risk AML • Secondary objectives: • Progression-free survival (PFS) • Overall survival (OS) • Duration of response • Safety

18. CTEP-20 Major Eligibility After amendment #6 • Inclusion: • Untreated newly diagnosed AML • > 75 • 65-74 with prior MDS • Confirmation with > 20% BM or PB blasts • PS 0 or 1, adequate renal and liver function. • Exclusion: circulating blasts > 30,000/uL, APL (M3), CNS leukemia, DIC

19. CTEP-20 Efficacy Assessment • Medical history and physical examination, BM aspirate and biopsy, hematological and chemistry labs at baseline and the end of each cycle • CR determined by NCI sponsored AML criteria (Cheson et al., J Clin Oncol 8: 813-819, 1990) • Subsequent treatment and follow up

20. CTEP-20 Efficacy

21. CTEP-20 Study Population *One elderly patient with AML did not receive treatment by the time of clinical cut off.

22. CTEP-20 Elderly Poor-Risk AML Population: Demographics a Some subjects had more than 1 reason for ineligibility for chemotherapy.

23. CTEP-20 Elderly Poor-Risk AML Population: Risk Factors

24. CTEP-20 Primary Endpoint: CR Rate

25. CTEP-20 CR Rate Analysis by FDA

26. CTEP-20 CR Rate Subgroup Analysis by FDA

27. CTEP-20 CR Duration

28. CTEP-20 Safety

29. CTEP-20 Safety – Exposure

30. CTEP-20 Safety – Dose Intensity

31. CTEP-20 Safety – Common AEs

32. CTEP-20 SafetyFrequent AEs Leading to Treatment Change

33. CTEP-20 Safety – Grade 3/4 AEs

34. CTEP-20 Safety - Death

35. CTEP-20 – Hospitalization on Study

36. SummaryZarnestra in Elderly Poor-Risk AML • Durable CR : an endpoint supportive of clinical benefit in AML • Consider in the context of : • 11.1% CRR with 275 days median duration • Poor risk patient population • 12% one-month death rate • 60% hospitalization

37. Question Does the risk benefit analysis support regular approval of Zarnestra for the first-line treatment of AML patients age 65 or older with prior MDS or age 75 and older?

38. Additional Slides

39. Standard Treatment Risk & Benefit in general and in elderly poor-risk AML patients: Summary

40. Zarnestra Risk & Benefit in elderly poor-risk AML patients compare to and Standard Treatment in elderly AML patients: Summary

41. Approvals for APL, MDS

42. Unfavorable Karyotype • Per the sponsor, the karyotypes described as unfavorable included: • del 5, del 5q, • del 7, del 7q, • trisomy 8, • 11q23, • complex (> 3 abnormalities).

43. Summary of Patients with or without Prior MDS

44. Sponsor’s RR by Risk Factors

45. CTEP-20: Complete Remission Criteria • Bone marrow < 5% myeloblasts with normal maturation of all cell lines, an ANC > 1000/uL, a platelet > 100, 000/uL, absence of blasts in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. • CR must be confirmed 4-6 weeks after initial documentation. At least one bone marrow biopsy should be performed to confirm CR. NCI-Sponsored Workshop on Definitions of Diagnosis and Response in Acute Myeloid Leukemia, 1990.

46. CTEP-20 Safety – Overall AEs

47. CTEP-20 Safety – Common Non Hem. AEs

48. CTEP-20 Safety – Common Hem & Met AEs

49. CTEP-20 SafetyAEs Leading to Treatment Termination

50. CTEP-20 Safety – AEs Leading to Dose Reduction (> 2%)