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Sipuleucel-T BLA 125197 FDA Clinical Review and Findings Ke Liu, MD, PhD Clinical Reviewer Division of Clinical Evaluati

Sipuleucel-T BLA 125197 FDA Clinical Review and Findings Ke Liu, MD, PhD Clinical Reviewer Division of Clinical Evaluation, Pharmacology and Toxicology (DCEPT), OCTGT, CBER, FDA March 29, 2007 Cellular, Tissue and Gene Therapies Advisory Committee Meeting. 1. Outline of Presentation.

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Sipuleucel-T BLA 125197 FDA Clinical Review and Findings Ke Liu, MD, PhD Clinical Reviewer Division of Clinical Evaluati

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  1. Sipuleucel-T BLA 125197 FDA Clinical Review and Findings Ke Liu, MD, PhD Clinical Reviewer Division of Clinical Evaluation, Pharmacology and Toxicology (DCEPT), OCTGT, CBER, FDA March 29, 2007 Cellular, Tissue and Gene Therapies Advisory Committee Meeting 1

  2. Outline of Presentation • Efficacy findings • Study design • Results • Safety findings • Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs) • Cerebrovascular Accidents (CVAs) --- Sponsor’s updated information 2

  3. Terminology of Presentation • Study Names • Study 1 = D9901 • Study 2 = D9902A • Study agents • Sipuleucel-T = APC8015 • Placebo = APC-Placebo • APC8015F = Frozen and thawed PBMC as source material, then prepared similarly as Sipuleucel T 3

  4. Basis for BLA submission:Overall Survival • Proposed Indication: Treatment of men with asymptomatic metastatic androgen independent prostate cancer (AIPC) • Basis of claim: • D9901: a 4.5-month overall survival difference • D9902A: a 3.3-month overall survival difference (not significant) 4

  5. D9901 and D9902A • Similarly designed randomized, double-blind, placebo-controlled trials in men with asymptomatic metastatic androgen independent prostate cancer. • Primary Endpoint: Time To Disease Progression • D9901 enrolled 127 subjects, 82 in Sipuleucel-T arm, 45 in Placebo • D9902A planned 120 subjects, but terminated early; 65 in Sipuleucel-T arm, 33 in Placebo • Study Period: • D9901, 01/00-09/04 • D9902A, 05/00-09/04 5

  6. Key Eligibility Criteria • Histologically documented adenocarcinoma of the prostate • Metastatic disease as evidenced by soft tissue and/or bony metastases. • PSA ≥ 5 ng/mL. • Tumor or PSA progression after hormonal therapy. • Castrate levels of testosterone (<50 ng/dl) • No cancer-related pain 6

  7. Treatment Schema P R O G R E S S I O N R A N D O M I Z E 2:1 Sipuleucel-T Q 2 wks x 3 (N = 82) Follow-up* Asymptomatic Metastatic AIPC (N = 127) (Optional use of APC8015F Q 2 wks x 3) Follow-up * Placebo Q 2wks x 3 (N = 45) *Post progression chemotherapy +/- other options allowed 7

  8. Treatment Regimen • Apheresis to harvest PBMCs, 2 to 3 days • prior to the infusion date • Sipuleucel-T or Placebo: 3 doses, q 2 wks, i.v. • The cell counts in each individual dose varied • depending on the apheresis yield. • Minimum for each dose of Sipuleucel-T was • approximately 3 X 106 CD54+ cells. • The dose for Placebo was 1/3 of the • total cells harvested from the apheresis. • Bisphosphonate allowed • Continued hormonal treatment 8

  9. Primary Endpoint Time to disease progression, as defined by time from randomization to the first observation of disease progression • Radiological Progression (Bone Scan q 8 wks, CT/MRI q 8 wks if baseline +) • New Cancer Related Pain (X-ray correlation required) • Clinical Events • Pathological Fracture, Cord or Nerve Root Compression • “Other Clinically-significant disease-specific events” 9

  10. Secondary Endpoints • Overall time from randomization to the development of disease-related pain • Overall time from randomization to earliest evidence of clinical progression • Rate of objective response • Duration of response • Time to treatment failure 10

  11. Statistical Assumptions • Median Time to Progression: • Based on the sponsor’s past experience and a review of the literature • Placebo: 16 weeks Sipuleucel-T: 31 weeks (HR = 1.92) • Alpha = 5% two-sided; 80% power • 2:1 Randomization 11

  12. D9901 Efficacy Results 12

  13. D9901 Patient Demographic and Baseline Characteristics Sipuleucel-T Placebo (n = 82) (n = 45) Median age (range) 73 yrs (47–85) 71 yrs (50–86) Ethnicity Caucasian 73 (89%) 42 (93.3%) African-American 8 (9.8%) 1 (2.2%) Hispanic 1 (1.2%) 1 (2.2%) Unknown 0 1 (2.2%) ECOG PS 0 62 (75.6%) 37 (82.2%) 1 20 (24.4%) 8 (17.8%) 13

  14. D9901 Patient Demographic and Baseline Characteristics (continued) Sipuleucel-T Placebo (n = 82) (n = 45) Gleason Score ≤ 6 n (%) 22 (26.8%) 7 (15.6%) = 7 n (%) 28 (34.1%) 18 (40%) ≥ 8 n (%) 32 (39%) 20 (44.4%) Disease location Bone only 34 (42.0%) 10 (23.8%) Soft tissue only 5 (6.2%) 3 (7.1%) Bone and soft tissue 42 (51.9%) 29 (69%) No. of bone metastases/subject 0 5 (6.1%) 4 (8.9%) 1-5 31 (37.8%) 17 (37.8%) 6-10 12 (14.6%) 12 (26.7%) > 10 34 (41.5%) 12 (26.7%) 14

  15. D9901 Primary Endpoint ---Time to Progression • 127 subjects randomized • 114 had progression event • 0 deaths prior to progression event • Progression documented by • Imaging: 97 • Clinical event: 10 • Onset of disease related pain correlated with imaging: 7 15

  16. 1st analysis after unblinding D9901: Time to Disease Progression • No statistical difference by Log-rank test: p = 0.085, HR = 1.39, 95% CI: 0.95, 2.03 • Median TTP • Sipuleucel-T: 11.1 weeks (range: 2.1 to 57.4) • Placebo: 9.1 weeks (range 3.9 to 52.1) 16

  17. Discussion --- D9901 Primary Endpoint (TTP) Result • After unblinding, the 1st analysis showed a log rank p-value for time to progression: 0.085 • Changed from 0.085 to 0.052 • Unblinded audit of clinical data • Primarily driven by two subjects 17

  18. Discussion continued ---D9901 Primary Endpoint (TTP) Result Difficulties in interpretation of TTP results: • Overestimation of TTP: • Assumption: 16 weeks for placebo and 31 weeks for Sipuleucel-T • Actual observation: 9-11 weeks for both arms • Median progression prior to scheduled second assessment for progression • Lack of scans to detect soft tissue progressions in some bone only subjects according to the study design • Un-interpretable progression dates in some subjects due to protocol violations 18

  19. Conclusion --- D9901 Primary Endpoint (TTP) • FDA considers the p-value of 0.085 by log-rank test to be the result from the primary analysis specified in the protocol and the p-value of 0.052 to be derived from an exploratory analysis. • The study failed to show a Sipuleucel-T treatment effect on the primary endpoint, TTP. 19

  20. D9901 Secondary Endpoints No difference observed between two arms for any of the following: • Overall time to the development of disease-related pain • Overall time to earliest evidence of clinical progression • Rate of objective response • Duration of response • Time to treatment failure 20

  21. D9901 Overall Survival 21

  22. D9901 Overall Survival *All subjects were followed for 36 months or until death # From available data 22

  23. Therapy After Progression D9901 • Chemotherapy • Placebo subjects “cross-over” to • APC8015F: 34/45 (75.6%) 23

  24. Potential Chemotherapy Confounding Effects on Overall Survival • Analysis of the time from randomization to 1st chemotherapy use did not suggest an earlier initiation of chemotherapy in Sipuleucel-T subjects • The dose and cycles of chemotherapy were not collected • Potential chemotherapy confounding effects on overall survival are unlikely, but cannot be ruled out 24

  25. D9901 Efficacy Summary • N = 127, randomized 2:1 to Sipuleucel-T (Sipuleucel-T) : Placebo • A small sample size • No difference between two arms in the pre-specified efficacy endpoints • Overall Survival: • 4.5-month difference in median survival in Sipuleucel-T arm (p = 0.010, HR 1.7) 25

  26. CD54 Upregulation and Survival Above the mean Below the mean 26

  27. Interpretation of CD54 Results • Intrinsic property of individual patients • Intrinsic property of individual products after manufacturing process. (Placebo did not undergo the same process as Sipuleucel-T) • Other factors? 27

  28. Immunological Analyses --- T cell Stimulation Index 28

  29. Interpretation of Stimulation Assays • Proliferation assay not a direct assay for T cell response • Assays performed only in a small subset of patients • No response to human PAP 29

  30. D9902A Efficacy Results 30

  31. Study D9902 • Same design as D9901 • Planned 120 subjects • Time To Disease Progression • as 10 endpoint Terminated (3/2003) Because of D9901 overall negative efficacy Renamed D9902A : 98 subjects already enrolled • D9902A • Insufficient sample size • Not powered to see a difference • in TTP or overall survival 31

  32. D9902A Patient Demographic and Baseline Characteristics Sipuleucel-T Placebo (n = 65) (n = 33) Median age (range) 70.0 yrs (51–84) 71.0 yrs (57–87) Ethnicity Caucasian 59 (90.8%) 31(93.9%) African-American 2 (3.1%) 2 (6.1) Hispanic 1 (1.5) 0 Other 3 (4.6) 0 ECOG PS 0 51 (78.5%) 23 (69.7%) 1 14 (21.5%) 10 (30.3%) 32

  33. D9902A Patient Demographic and Baseline Characteristics (continued) Sipuleucel-T Placebo (n = 65) (n = 33) Gleason Score ≤ 6 n (%) 15 (23.4%) 9 (27.3%) = 7 n (%) 29 (45.3%) 8 (24.2%) ≥ 8 n (%) 20 (31.3%) 16 (48.5%) Disease location Bone only 31 (47.7%) 10 (30.3%) Soft tissue only 7 (10.8%) 7 (21.2%) Bone and soft tissue 27 (41.5%) 16 (48.5%) No. of bone metastases/subject N = 61 N = 32 0 5 (8.2%) 4 (8.9%) 1-5 19 (31.1%) 11 (34.4%) 6-10 6 (9.8%) 2 (6.3%) > 10 31 (50.8%) 12 (37.5%) 33

  34. D9902A Time to Disease Progression • The estimated median TTP: • 10.9weeks in the Sipuleucel-T arm (Range 3.4 to 106.6 wks) • 9.9 weeks in the APC placebo arm (Range 1.7 to 130.1 wks) 34

  35. D9902A Overall Survival Median survival time (MST) Estimates: Sipuleucel-T: 19.0 months (13.6, 31.9) Placebo 15.7 months (12.8, 25.4) 35

  36. D9902A Efficacy Summary • N = 98, randomized 2:1 to Sipuleucel-T: Placebo • Similar trial design and execution as D9901 • Stopped early. Insufficient sample size to detect a difference in TTP or overall survival • No statistical difference in time to progression, overall survival between treatment arms 36

  37. Safety Evaluation • Main analyses from D9901and D9902A database: • 146 subjects received Sipuleucel-T • 76 subjects received Placebo • Cerebrovascular accidents (CVA) events from an updated database including other phase 3 trials, D9902B and P-11 • Complete safety database update was submitted last week to include a total of 461 subjects who received Sipuleucel T and 231 subjects who received Placebo 37

  38. Infusion Exposure (D9901 and D9902A) 38

  39. Death (D9901 and D9902A) # Included one death from each of the following in Sipuleucel-T arm: Cardiac Arrest; Dementia; Glioblastoma; Met. Esophageal Ca; Orthopedic Complication; Renal Failure; Sepsis and ARDS; UTI; one death from Small Cell Carcinoma In Placebo 39

  40. SAEs* (≥ 2%, D9901 and D9902A) *Other than Death 40

  41. Common Adverse Events in D9901 and D9902A* * >10 % in Sipuleucel T subjects #Adverse events that occurred more often in Sipuleucel-T subjects @ Subjects who had at least one leukapheresis 41

  42. Trials Subjects for CVA Analyses 42

  43. CVA Events 43

  44. Safety Conclusions • Almost all Sipuleucel-T treated subjects developed Adverse Events (98.6% Sipuleucel-T versus 96.1% placebo). • Most AEs were grade 1 to 2 and resolved within 48 hours. • 24% Sipuleucel-T subjects developed SAEs, not different from 23% of Placebo treated subjects. • Although the differences did not reach statistical significance, the increased CVA events observed in Sipuleucel-T subjects is a potential safety signal. 44

  45. Conclusions --- Efficacy • Neither study met pre-specified efficacy endpoint • Survival analyses • D9901: a 4.5-month overall survival difference. Statistically significant by log-rank test • D9902A: a 3.3-month overall survival difference --- Not statistically significant 45

  46. Discussion --- Overall Survival in Cancer Clinical Trials • The most reliable cancer endpoint • Usually the preferred endpoint when studies can be conducted to adequately assess it. • An improvement in survival is a clinical benefit. • The endpoint is precise and easy to measure, documented by the date of death.  Bias is not a factor in endpoint measurement. • Demonstration of a statistically significant improvement in overall survival has supported new drug approvals 46

  47. Discussion --- Overall Survival Difference in D9901 • 4.5 month median survival difference is Clinically meaningful • Limitations of survival result • Post hoc analyses • Survival not the pre-specified endpoint • Primary method for survival analysis not pre-specified • One study with a small sample size • Difference could be due to chance 47

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