Food and Drug Administration

Center for Biologics Evaluation and Research

Cellular, Tissue and Gene Therapies Advisory Committee

Meeting # 43

March 29, 2007

PROVENGE^® (Sipuleucel T)

BLA # 125197

Draft Advisory Committee Questions

Proposed indication: For the treatment of men with asymptomatic metastatic androgen independent prostate cancer (AIPC).

1. The manufacturing process for sipuleucel-T (APC-8015) was designed to significantly reduce red blood cells and granulocytes from the starting autologous apheresis material. A decrease in the numbers of T cells, B cells, NK cells, and monocyte populations is observed after each of the major manufacturing steps. However, the relative percentages of the populations do not change significantly at any step. Each apheresis collected varies in cell number and percent of specific cell types. There are no minimum or maximum limits for total cell number in the final product. Dosing is based on a minimum number of total nucleated cells in the cellular starting material and a minimum number of CD54+ cells in the final product. Thus, lots of sipuleucel-T (APC-8015) vary in total cell number and number of T, B, and NK cells, and monocyte populations.

• Please discuss whether/how the variability in each product dose, in respect to total cell number and range in cell ratios, can be expected to affect product quality, safety, or effectiveness.

2. For sipuleucel-T (APC-8015), potency is determined by measuring both the number of CD54 positive cells and the up-regulation of CD54 expression on those cells after exposure to antigen. The proposed mechanism of action of sipuleucel-T (APC-8015) is presentation of PAP antigen by activated APC to stimulate tumor-specific T cells in the patient. The applicant provided data that shows CD54 positive cells in sipuleucel-T (APC-8015) are antigen presenting cells (APC) and can induce antigen-specific IL-2 production by T cell clones in vitro. They also provided data that correlates increased CD54 upregulation with the ability of APC to elicit allogeneic T cell proliferation. In addition to APC, the final product also contains B cells, NK cells, and T cells, with T cells typically being the largest cell population in the final product.

• Please discuss whether/how the data support the conclusion that the primary mode of action is APC function. Please discuss the data that support increased CD54 expression as a measure of APC activation.

3. The applicant performed immune monitoring in a limited number of patients during clinical development. The immune monitoring included measuring T cell proliferation in vitro and antibody titers in vivo to both PA2024 and seminal PAP. The sponsor also measured NK cell lytic activity against a cell line sensitive to NK cell lysis.

• Please discuss the immune monitoring data provided by the applicant. Please provide suggestions for immune monitoring data that could be collected in future studies.

4. Based on the data presented, please discuss whether you consider cerebrovascular accidents (CVA) to be a potential safety signal. Please discuss possible additional studies to further characterize this finding.

Table 1: CVA Events

Studies Included	sipuleucel-T (APC-8015)	Placebo	Odds Ratio
	n / N (%)	n / N (%)	(95% CI)	p-value^a
Randomized studies ^b	18 / 461 (3.9%)	6 / 231 (2.6%)	1.52 (0.6, 3.9)	0.5
AIPC ^c	17 / 345 (4.9%)	3 / 172 (1.7%)	2.92 (0.84, 10)	0.092
ADPC ^d	1/116 (0.9%)	3 / 59 (5.1%)	0.16 (0.02, 1.6)	0.11
Deaths attributed to CVAs	7 / 461 (1.5%)	2 / 231 (0.9%)	1.76 (0.36, 8.6)	0.725
Hemorrhagic	3 / 461 (0.6%)	1 / 231 (0.4%)	1.51 ( 0.16, 14.56)	1.00
Ischemic	11/461(2.4%)	5/231(2.2%)	1.10(0.38,3.22)	1.00
Unknown	4/461 (0.9%)	0/231 (0.0%)	-	0.307

a: Fisher’s Exact 2- sided test; b: D9901, D9902A, P-11 and D9902B; c: Androgen Independent Prostate Cancer: D9901, D9902A, and D9902B; d: Androgen Dependent Prostate Cancer : P-11

5. The efficacy claim contained in this BLA is based on an observed survival difference between those patients treated with sipuleucel-T (APC-8015) compared with those treated with placebo in study 1 (D9901). However, studies 1 (D9901) and 2 (9902A) failed to achieve any of their primary or secondary objectives. Please discuss the persuasiveness of the efficacy evidence reported in the BLA (Table 2).

Table 2: Summary of Efficacy reported in the BLA

Study	Median Time to Progression (weeks) Sipuleucel-T Placebo	Median Survival (months) Sipuleucel-T Placebo
1 (D9901)	11.0 9.1 (p = 0.085)	25.9 21.4 (p = 0.010)
2 (D9902A)	10.9 9.9 (p = 0.719)	19.0 15.7 (p = 0.331)

6. The Study population in study 1 (D9901) was approximately 90% Caucasian. Please discuss the generalizablity of these study results to other ethnic populations.

Voting Questions

7. Does the submitted data establish that sipuleucel-T (APC-8015) is reasonably safe for the intended population?

8. Does the submitted data establish the efficacy of sipuleucel-T (APC-8015) in the intended population?