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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
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
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)
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
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
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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”
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
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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
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17	Discussion --- D9901 Primary Endpoint (TTP) Result After unblinding, the 1^st 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
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
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.
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
21	D9901 Overall Survival
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23	Therapy After Progression D9901
24	Potential Chemotherapy Confounding Effects on Overall Survival Analysis of the time from randomization to 1^st 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
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)
26	CD54 Upregulation and Survival
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?
28	Immunological Analyses --- T cell Stimulation Index
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
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31	Study D9902
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35	D9902A Overall Survival
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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
38	Infusion Exposure (D9901 and D9902A)
39	Death (D9901 and D9902A)
40	SAEs^* (≥ 2%, D9901 and D9902A)
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42	Trials Subjects for CVA Analyses
43	CVA Events
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.
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
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
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