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

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

3. 3 Regulatory Background

4. 4 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 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 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 In some cases where leukemia CR’s were of uncertain duration, CR was considered a surrogate reasonably likely to predict CB

5. 5 Drug Approvals for AML

6. 6 Clinical Overview

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

8. 8 Induction Chemotherapy for Elderly Patients with AML Age65-74 years (N=1,132) 75-84 years (N=1,082) >85 years (N=433) Total (N=2,657) Received chemotherapy 44%24%6%30% Menzin et al., Arch Intern Med 2002, 162: 1597.

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

10. 10 Elderly Patients with Poor-Risk AML Higher mortality and morbidity seen in elderly patients with poor-risk AML receiving standard chemotherapy Higher mortality and morbidity seen in elderly patients with poor-risk AML receiving standard chemotherapy OutcomeAge < 65Age >65 + Other factors Treatment related death10-20%> 25% Complete remission rate60-75%30% - 50% Survival rate30-40% > 3 years< 6% at 2 years

11. 11 Clinical Program

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

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

14. 14 Zarnestra NDA: AML Trials Clinical Study Elderly poor-risk AML / AML (Total Enrolled) Study DescriptionEndpoints CTEP-20*136 / 157 (N=171) Single arm, open label, previously untreated elderly poor-risk AML patients Efficacy and safety INT-1799 / 252 (N= 252) Single arm, open label, refractory or relapsed AML patients Efficacy, safety, and PK CTEP-1*14 / 25 (N = 34) Single arm, open label, dose escalation in hematologic malignancies Phase 2 recommended dose, PK and tolerability * Conducted by NCI, CTEP as part of a Cooperative Research and Development Agreement with J&J

15. 15 CTEP-20 Design

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

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

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

19. 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 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 CR determined by NCI sponsored AML criteria (Cheson et al., J Clin Oncol 8: 813-819, 1990) Subsequent treatment and follow up Subsequent treatment and follow up

20. 20 CTEP-20 Efficacy

21. 21 CTEP-20 Study Population *One elderly patient with AML did not receive treatment by the time of clinical cut off. Patient Population Number of Patients SponsorFDA All Enrolled171 All Treated AML157156 Elderly poor-risk AML Age  75 years Age 65-74 years with prior MDS 136 75 61 135 74 61 Non AML13 (8) 14 (8) MDS b 8 (5) 9 (5) CMML 5 (3)

22. 22 CTEP-20 Elderly Poor-Risk AML Population: Demographics Number of subjects (%)65-74 y prior> 75 yTotal Baseline ECOG performance status 6073133 019 (32)13 (18)32 (24) 135 (58)51 (70)86 (65) 26 (10)9 (12)15 (11) Ineligible for chemotherapy a 6175136 Age34 (56)72 (96)106 (78) Risk factors31 (51)29 (39)60 (44) Other15 (25)10 (13)25 (18) a Some subjects had more than 1 reason for ineligibility for chemotherapy.

23. 23 CTEP-20 Elderly Poor-Risk AML Population: Risk Factors Risk factor65-74 y prior MDS (N= 61) n (%) > 75 y (N= 75) n (%) Total (N= 136) n (%) Prior MDS61 (100)50 (67)111 (82) Baseline organ dysfunction31 (51)52 (69)83 (61) Age > 75 years-75 (100)75 (55) Unfavorable karyotype37 (61)29 (39)66 (49) Number of risk factors per subject 110 (16)4 (5)14 (10) 234 (56)26 (35)60 (44) 317 (28)30 (40)47 (35) 4-15 (20)15 (11)

24. 24 CTEP-20 Primary Endpoint: CR Rate Total (N= 135) CR (%)CRuUnavailable for Assessment Investigators17 (13)21 Independent Review 15 (11)32 FDA15 (11)32

25. 25 CTEP-20 CR Rate Analysis by FDA Confirmed CR / No. of Patients CR Rate (n/N) [95% CI] 15 / 13511.1% 6.6 – 18.0%

26. 26 CTEP-20 CR Rate Subgroup Analysis by FDA CategoryGroup Confirmed CR / No. of Patients CR Rate (n/N) [95% CI] Age 65 – 74 years10 /61 16.4% 8.6 – 28.5% ≥ 75 years5 / 74 6.8% 3.1 – 18.8% Prior MDS Yes14 / 110 12.7% 7.4 – 20.8% No1 / 25 4% 0.2 – 22.3% Karyotype Unfavorable5 / 65 7.7% 0.1 – 9.4 Favorable9 / 62 14.5% 0.1 – 19.8 Unkown1 / 8 12.5% 0.7 – 53.3%

27. 27 CTEP-20 CR Duration AnalysisFDA Results Number failed/Number assessed7/15 (47%) Median duration in days [95% CI] 275 [127 – 376]

28. 28 CTEP-20 Safety

29. 29 CTEP-20 Safety – Exposure Category, n (%)Cycle 1 136 (100) Cycle 2 64 (47) Cycle 3 27 (20) Cycle duration 1-28 days39 (29)13 (20)7 (26) 29-35 days21 (15)12 (19)5 (19) 36-42 days29 (21)19 (30)8 (30) 43-49 days26 (19)10 (16)5 (19) 50-56 days7 (5)4 (6)- 57- 63 days6 (4)3 (5)1 (4) > 64 days8 (6)3 (5)1 (4) Mean (SD)36.8 (16.88)37.6 (15.06)36.4 (14.39) Median38 36 Range(3; 92)(5; 75)(10; 85)

30. 30 CTEP-20 Safety – Dose Intensity CategoryCycle 1 (N= 136) Cycle 2 (N= 64) Cycle 3 (N= 27) Dose intensity, mg/day Mean (SD)749.4 (277.40)597.3 (251.93)631.2 (282.9) % of planned635053 Median663.2566.4586.1 Range(273.9; 1200.0)(168.0; 1200.0)(197.6; 1200.0)

31. 31 CTEP-20 Safety – Common AEs Non- Hematologic diarrhea, fatigue, nausea, skin rash, fever, anorexia, constipation, vomiting, dyspnea, dizziness, ataxia or abnormal gait, confusion, bacterial infection, fungal infection Hematologicneutropenia with or without fever, purpura, thrombocytopenia, anemia Metabolicincreased creatinine, hypokalemia, hyponatremia

32. 32 CTEP-20 Safety Frequent AEs Leading to Treatment Change Treatment Change Incidence (n=136, %) Most Frequent AEs Termination21 (15)increased creatinine, rash, increased pancreatic enzymes Dose Reduction 47 (35)neutropenia, ataxia, increased creatinine or abnormal renal function, confusion, diarrhea, increased pancreatic enzymes, rash Interruption56 (41)neutropenia, increased creatinine, nausea/vomiting, rash, confusion, pancytopenia

33. 33 CTEP-20 Safety – Grade 3/4 AEs WHO Preferred TermTotal N= 136 (%) Total no. subjects113 (83) Neutropenia febrile40 (29) Infection bacterial25 (18) Thrombocytopenia23 (17) Neutropenia without fever16 (12) Pneumonia14 (10) Creatinine increased12 (9) Rash12 (9) Anemia11 (8) Diarrhea8 (6) Hypokalemia8 (6)

34. 34 CTEP-20 Safety - Death Cause of DeathTotal N= 136 (%) Deaths during the study31 (23) Progressive disease19 (14) Adverse event9 (7) Drug related1 (1) Other3 (2) Early deaths16 (12)

35. 35 CTEP-20 – Hospitalization on Study No. of patient treated136 Total no. of hospitalizations141 No. of subjects hospitalized during study, n (%)81 (60) 1-2 hospitalizations71 (52) 3-4 hospitalizations8 (6) > 5 hospitalizations2 (1) Total duration of hospitalization, days N81 Mean (SD)17.9 (14.38) Median15.0 Range(2; 73)

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

37. 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. 38 Additional Slides

39. 39 Summary Standard Treatment Risk & Benefit in general and in elderly poor-risk AML patients: Standard Treatment Risk & Benefit in general and in elderly poor-risk AML patients: Outcome versus Age< 65>65 + Poor-risk Treatment related death10-20%> 25% Complete remission rate60-75%30% - 50% 2 year survival rate30-40% > 3 years< 6% at 2 year

40. 40 Summary Zarnestra Risk & Benefit in elderly poor-risk AML patients compare to and Standard Treatment in elderly AML patients: Zarnestra Risk & Benefit in elderly poor-risk AML patients compare to and Standard Treatment in elderly AML patients: Outcome versus TxZarnestraStandard Complete remission rate11.1%30% - 50% Treatment related death7%> 25% One month mortality12%30- 48%

41. 41 Approvals for APL, MDS

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

43. 43 Summary of Patients with or without Prior MDS Population < 65 years n (%) 65-74 years n (%)  75 years n (%) Total n (%) All Treated AML7/9 (78%)61/73 (84%)49/74 (66%) 117/156 (75%) Elderly Poor-Risk AML 0/0 61/61 (100%) 49/74 (66%) 110/135 (81%) Per Protocol0/0 48/48 (100%) 41/55 (75%) 89/103 (86%)

44. 44 Sponsor’s RR by Risk Factors TotalCRPR Age13620 (15)3 (2) 65-74 y6111 (18)3 (5) > 75 y759 (12)- Karyotype unfavorable13620 (15)3 (2) Yes669 (14)3 (5) No6210 (16)- Not done / not available81 (13)- Organ dysfunction13620 (15)3 (2) Yes8313 (16)2 (2) No537 (13)1 (2) Prior MDS13620 (15)3 (2) Yes11118 (16)3 (3) No252 (8)-

45. 45 CTEP-20: Complete Remission Criteria Bone marrow 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. Bone marrow 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. 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. 46 CTEP-20 Safety – Overall AEs Number (%) of Subjects With:Elderly Poor- Risk AMLAll- Treated AML 65-74 y prior MDS N = 61 (%) > 75 y N = 75 (%) Total N= 136 (%) Total (N= 157) (%) AEs60 (98)74 (99)134 (99)155 (99) Drug-related AEs53 (87)65 (87)118 (87)134 (85) Grade 3 or 4 AEs51 (84)62 (83)113 (83)131 (83) Drug- related grade 3 or 4 AEs37 (61)46 (61)83 (61)92 (59) SAEs38 (62)50 (67)88 (65)103 (66) Drug- related SAEs23 (38)35 (47)58 (43)64 (41) AEs leading to treatment termination 11 (18)10 (13)21 (15)26 (17) Drug- related AEs leading to treatment termination a 7 (11)7 (9)14 (10)18 (11) Deaths due to an AE2 (3)7 (9)9 (7)11 (7) Drug- related AEs resulting in death 01 (1) Early deaths due to an AE2 (3)3 (4)5 (4)6 (4)

47. 47 CTEP-20 Safety – Common Non Hem. AEs WHO Preferred TermTotal N= 136 (%) Diarrhea64 (47) Fatigue60 (44) Nausea51 (38) Rash48 (35) Fever42 (31) Anorexia37 (27) Constipation33 (24) Vomiting32 (24) Dyspnea32 (24) Dizziness36 (26) Ataxia + abnormal gait27 (20) Confusion29 (21)

48. 48 CTEP-20 Safety – Common Hem & Met AEs WHO Preferred TermTotal N= 136 (%) Neutropenia febrile40 (29) Purpura29 (21) Thrombocytopenia26 (19) Anemia24 (18) Neutropenia17 (13) Infection bacterial27 (20) Moniliasis and other fungal infection22 (16) Creatinine62 (46) Hypokalemia59 (43) Hyponatremia57 (42)

49. 49 CTEP-20 Safety AEs Leading to Treatment Termination WHO Preferred TermTotal N= 136 (%) AllDrug Related Total no. subjects with AE21 (15)14 (10) Creatinine blood increased4 (3)3 (2) Rash4 (3)3 (2) Pancreas enzymes increased2 (1) Dehydration1 (1) Diarrhea1 (1) Dizziness1 (1) Fatigue1 (1) Insomnia1 (1) Nausea1 (1) Neuropathy peripheral1 (1) Sweating increased1 (1)

50. 50 CTEP-20 Safety – AEs Leading to Dose Reduction (> 2%) WHO Preferred TermTotal (N= 136) (%) AllDrug Related Total no. subjects with AE47 (35)35 (26) Neutropenia febrile9 (7)6 (4) Ataxia5 (4) Creatinine blood increased6 (4)4 (3) Confusion6 (4)3 (2) Diarrhea4 (3)3 (2) Neutropenia4 (3)3 (2) Pancreas enzymes increased3 (2) Rash5 (4)3 (2) Renal function abnormal3 (2) Amnesia2 (1) Bilirubinemia3 (2)2 (1) Fatigue2 (1) Hypotension postural2 (1) Infection bacterial3 (2)2 (1)

51. 51 CTEP-20 Safety – AEs Causing Treatment Interuption (> 2%) WHO Preferred TermTotal N= 136 (%) AllDrug Related Total no. subjects with AE56 (41)45 (33) Neutropenia10 (7)8 (6) Creatinine blood increased10 (7)7 (5) Nausea6 (4) Neutropenia febrile8 (6)6 (4) Rash5 (4) Confusion3 (2) Pancytopenia4 (3)3 (2) Vomiting3 (2) Ataxia2 (1) Bilirubinemia3 (2)2 (1) Diarrhea3 (2)2 (1) Gait abnormal2 (1) Infection bacterial3 (2)2 (1) Infection fungal2 (1) Neuropathy peripheral2 (1) Pneumonia4 (3)2 (1)

52. 52 CTEP-20 Safety – A Es Associated with Death WHO Preferred TermTotal N= 136 (%) Total no. subjects who died9 (7) Cardiac failure3 (2) Sepsis3 (2) Infection fungal2 (1) Pneumonia2 (1) Arrhythmia atrial1 (1) Circulatory failure1 (1) Fibrillation atrial1 (1) Gastrointestinal hemorrhage1 (1) Hypoxia1 (1) Multiple organ failure1 (1) Neutropenia febrile1 (1) Pulmonary hemorrhage1 (1) Renal failure acute1 (1)

53. 53 CTEP-20: Concomitant Therapy During Treatment Total N= 136 (%) Blood product transfusions119 (88) Human RBCs a 114 (84) Platelets, human blood89 (65) White blood cells3 (2) Anti-infectives116 (85) Antibiotics111 (82) Antivirals71 (52) Antifungals51 (38) Hydroxyurea3 (2) Growth factors12 (9)

54. 54 CTEP-20 – Reason for Hospitalization Reason for hospitalization, N = 136 (%) No. of subjects with recorded reason81 (59) AE related to study medication51 (38) AE related to disease33 (24) Other reason18 (13) Chemotherapy2 (1) Transfusion2 (1) AE related to medication (not tipifarnib)2 (1)

55. 55 Sponsor’s Response Rate in Relapsed AML INT-17 and CTEP-1 ResponseINT-17 (N= 99) CTEP -1 (N= 22) CR2 (2%)2 (9%) PR6 (6%)6 (27%)