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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

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

fda presenters
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

sipuleucel t review team
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

manufacturing process overview sipuleucel t apc8015
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

manufacturing process overview placebo apc placebo
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

slide6

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)

slide7

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)

the manufacturing process
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

numbers of cells infused are highly variable
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

evidence for cellular activation and antigen presentation
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

monocytes take up antigen
Monocytes take up antigen

Cell type specific marker

Antigen uptake

13

evidence for cellular activation and antigen presentation15
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

evidence for cellular activation and antigen presentation17
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

product potency
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

limitations of the potency assay
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

summary
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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