Sipuleucel-T BLA 125197

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Sipuleucel-T BLA 125197
Cellular, Tissue and Gene Therapies Advisory
Committee Meeting

• US Food and Drug Administration
• Center for Biologics Evaluation and Research

March 29, 2007
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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

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Sipuleucel-T Review Team
Pharmacology and Toxicology Yongjie Zhou, MD,
PhD Bioresearch Monitoring Bhanu
Kannan Epidemiology Kathryn OConnell, 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 Cather
ine Miller
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Manufacturing Process OverviewSipuleucel-T
(APC8015)
Further enrichment of mononuclear cells
Collects patients blood cells
PA2024 ANTIGEN ADDED
APC activation/antigen processing
3-4 Days
Final formulation
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Manufacturing Process OverviewPlacebo
(APC-Placebo)
Enriches for mononuclear cells
Collects patients WBC
REFRIGERATEDNo PA2024 antigen added
NO APC activation
Final formulation
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Apheresis (APH)
Buoyant Density Centrifugation Steps (BDS77 and
BDS65)
In vitro culture
Final product formulation (FP)
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Apheresis (APH)
Buoyant Density Centrifugation Steps (BDS77 and
BDS65)
PA2024
In vitro culture
Final product formulation (FP)
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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

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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

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Relative percentages of cell types are highly
variable
Monocyte CD14, CD54
B cell CD19
T cell CD3
NK cell CD56
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Proposed mechanism of action
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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
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Monocytes take up antigen
Cell type specific marker
Antigen uptake
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Monocytes express CD54
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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
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Costimulatory molecule expression increases
during culture with PA2024
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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
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CD54 positive cells stimulate PAP-specific T cell
clones
Number of Cells
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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

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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 patients prostate
  cancer is unknown

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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

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