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Sipuleucel-T BLA 125197

Sipuleucel-T BLA 125197. US Food and Drug Administration Center for Biologics Evaluation and Research. Cellular, Tissue and Gene Therapies Advisory Committee Meeting. March 29, 2007. 1. FDA Presenters. Keith Wonnacott, PhD, Product Reviewer Division of Cellular and Gene Therapies

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Sipuleucel-T BLA 125197

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  1. Sipuleucel-TBLA 125197 US Food and Drug Administration Center for Biologics Evaluation and Research Cellular, Tissue and Gene Therapies Advisory Committee Meeting March 29, 2007 1

  2. FDA Presenters Keith Wonnacott, PhD, Product Reviewer Division of Cellular and Gene Therapies Office of Cellular, Tissue and Gene Therapies Ke Liu, MD, PhD, Clinical Reviewer Division of Clinical Evaluation, Pharmacology and Toxicology Office of Cellular, Tissue and Gene Therapies BoGuang Zhen, PhD, Statistical Reviewer Division of Biostatistics Office of Biostatistics and Epidemiology 2

  3. Sipuleucel-T Review Team Pharmacology and Toxicology Yongjie Zhou, MD, PhD Bioresearch Monitoring Bhanu Kannan Epidemiology Kathryn O’Connell, MD, PhD Manufacturing and Product Quality Gang Wang, PhD Mary Padgett Project Management Lori Tull, RAC Mark Davidson Product Keith Wonnacott, PhD Thomas Finn, PhD Malcolm Moos, MD, PhD Syed Husain, PhD Clinical Ke Liu, MD, PhD Peter Bross, MD Statistics BoGuang Zhen, PhD Labeling Catherine Miller

  4. Manufacturing Process Overview:Sipuleucel-T (APC8015) Further enrichment of mononuclear cells Collects patient’s blood cells PA2024 ANTIGEN ADDED APC activation/antigen processing 3-4 Days Final formulation 4

  5. Manufacturing Process Overview:Placebo (APC-Placebo) Enriches for mononuclear cells Collects patient’s WBC REFRIGERATED—No PA2024 antigen added NO APC activation Final formulation 5

  6. Granulocytes Monocyte Red Blood Cells Platelets Neutrophil Eosinophil Basophil B cell T cell NK cell Apheresis (APH) Buoyant Density Centrifugation Steps (BDS77 and BDS65) In vitro culture 6 Final product formulation (FP)

  7. Monocyte B cell T cell NK cell Apheresis (APH) Buoyant Density Centrifugation Steps (BDS77 and BDS65) PA2024 In vitro culture 7 Final product formulation (FP)

  8. The Manufacturing Process: • IS designed to: • Enrich for mononuclear leukocytes • Activate antigen presenting cells • IS NOT designed to : • Control cell number • Control relative percentages of cell types 8

  9. Numbers of cells infused are highly variable • Minimum total nucleated cell (TNC) number required for APH starting material • Process significantly reduces TNC number • No upper or lower limit for TNC in the final product 9

  10. Relative percentages of cell types are highly variable 10

  11. During manufacturing In the patient Proposed mechanism of action 11

  12. Evidence for cellular activation and antigen presentation Monocytes take up the antigen and express the cell surface marker CD54 Antigen presenting cells show increased expression of costimulatory molecules CD54 expressing cells present antigen to antigen-specific T cell clones 12

  13. Monocytes take up antigen Cell type specific marker Antigen uptake 13

  14. Monocytes express CD54 14

  15. Evidence for cellular activation and antigen presentation Monocytes take up the antigen and they express the cell surface marker CD54 Antigen presenting cells show increased expression of costimulatory molecules CD54 expressing cells present antigen to antigen-specific T cell clones 15

  16. Costimulatory molecule expression increases during culture with PA2024 16

  17. Evidence for cellular activation and antigen presentation Monocytes take up the antigen and they express the cell surface marker CD54 Antigen presenting cells show increased expression of costimulatory molecules CD54 expressing cells present antigen to T cells 17

  18. CD54 positive cells stimulate PAP-specific T cell clones Number of Cells 18

  19. Product Potency • Potency assay is designed to detect activated antigen presenting cells • Product potency measures: • Number of CD54 positive cells • indirect indication that cells can process and present antigen • CD54 upregulation • ratio of CD54 expression before and after culture with PA2024 • direct measure of cellular activation 19

  20. Limitations of the potency assay • Impact of manufacturing on other cell types and the potential role of other cell types is unknown • CD54 cells typically represent only 20% of final product • Roles of B cells, T cells and NK cells are unknown • The ability of sipuleucel-T (APC8015) to induce an immune response against the patient’s prostate cancer is unknown 20

  21. Summary • Cell number varies • Relative percentages of cells vary • Sipuleucel-T contains activated antigen presenting cells that can process and present the tumor antigen • The contribution of other cells to product activity is not known 21

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