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					          U.S. Food and Drug Administration
          CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


Cellular, Tissue and Gene Therapies Advisory Committee Meeting




                                 Sipuleucel-T
                                       BLA 125197
                          US Food and Drug Administration
                          Center for Biologics Evaluation and
                                       Research



                           March 29, 2007
                                                                 1
           U.S. Food and Drug Administration
           CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




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
             U.S. Food and Drug Administration
             CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




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



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
            U.S. Food and Drug Administration
            CENTER FOR BIOLOGICS EVALUATION AND RESEARCH



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
                      U.S. Food and Drug Administration
                      CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

                                        Apheresis (APH)
                                     Granulocytes




Red Blood Cells   Platelets   Neutrophil Eosinophil   Basophil   Monocyte   B cell   T cell   NK cell

              Buoyant Density Centrifugation Steps (BDS77 and BDS65)




                                         In vitro culture




                                Final product formulation (FP)                                      6
    U.S. Food and Drug Administration
    CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

                       Apheresis (APH)




Buoyant Density Centrifugation Steps (BDS77 and BDS65)
                                                   PA2024




            Monocyte   B cell   T cell   NK cell

                       In vitro culture




              Final product formulation (FP)                7
       U.S. Food and Drug Administration
       CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




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
      U.S. Food and Drug Administration
      CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


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
      U.S. Food and Drug Administration
      CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


Relative percentages of cell types
are highly variable

                                                     Monocyte
                                                     CD14, CD54




                                                       B cell
                                                       CD19




                                                       T cell
                                                        CD3




                                                      NK cell
                                                       CD56 10
     U.S. Food and Drug Administration
     CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




Proposed mechanism of action

                                                    During
                                                    manufacturing




                                                    In the patient

                                                                     11
      U.S. Food and Drug Administration
      CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


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
                               U.S. Food and Drug Administration
                               CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




           Monocytes take up antigen
Cell type specific
marker




                     Antigen
                     uptake




                                                                              13
     U.S. Food and Drug Administration
     CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




Monocytes express CD54




                                                    14
      U.S. Food and Drug Administration
      CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


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
                                         U.S. Food and Drug Administration
                                         CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


 Costimulatory molecule expression
 increases during culture with PA2024
                        60




                                                                                                                                                    60
                                                                 60




                                                                                                           60
                   Counts




                                                                                                                                               Counts
                                                            Counts




                                                                                                      Counts
Day 0
                        0




                                                                                                                                                    0
                                                                 0




                                                                                                           0
                             100   101    102   103   104             100   101   102   103   104               100   101    102   103   104             100   101    102   103   104
                        60




                                                                 60




                                                                                                                                                    60
                                                                                                           60
                   Counts




                                                            Counts




                                                                                                                                               Counts
                                                                                                      Counts
Day 2
                        0




                                                                 0




                                                                                                                                                    0
                                                                                                           0
                             100   101    102   103   104             100   101   102   103   104               100   101    102   103   104             100   101    102   103   104
   # of cells




                                         CD54                                HLA-DR                                         CD86                                     CD40
                                                                              (MHC)

                                                                                                    Small, et. al. 2000, J. Clinic. Oncology 18:3894
                Increased expression

                                                                                                                                                                                        16
      U.S. Food and Drug Administration
      CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


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
      U.S. Food and Drug Administration
      CENTER FOR BIOLOGICS EVALUATION AND RESEARCH


CD54 positive cells stimulate PAP-
specific T cell clones




                     Number of Cells                 18
       U.S. Food and Drug Administration
       CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




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
        U.S. Food and Drug Administration
        CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




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
       U.S. Food and Drug Administration
       CENTER FOR BIOLOGICS EVALUATION AND RESEARCH




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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