Human Embryonic Stem Cells: Considerations for Therapeutic Development

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Human Embryonic Stem Cells Considerations for
Therapeutic Development
Jane Lebkowski Ph.D. Geron Corporation Cell,
Tissue and Gene Therapy Advisory Committee
Meeting April 10, 2008
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Human Embryonic Stem Cells
Large Characterized cGMP Banks
Therapeutic Cells
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hESCs New Cell Type for Potential Broad
Therapeutic Application

• Simplify, Standardize, and Scale hESC Growth
• Develop Reproducible Methods to Selectively
  Differentiate Cells
• Develop Parameters to Characterize Differentiated
  Cell Populations
• Define Efficacy, Potency, Safety of Cell
  Populations
• Develop Methods to Deliver Cells to Target Tissue
• Define Need for Immunosuppression
• Demonstrate Safety Efficacy in Clinical Trials
• Develop Scaled Low Cost Production Methods

Necessary Technological Developments
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Spinal Cord Injury GRNOPC1 Transplantation
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Differentiation Process

• Characterization of Materials
• Starting Material
• Adventitious Agents
• Characterization of Unit Operations
• Cell Density
• Culture Format
• Timing of Induction
• Storage
• Release Testing

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GRNOPC1 Contains Oligodendroglial Progenitors
Phenotype Testing of Over 75 Lots
Identity Purity Strength Potency
Challenges

• Multiple Markers Required
• Lineage Specific Markers
• Specific Antibodies
• Detection and Quantitation Limits of Assays
• Potency Assays

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Considerations for Nonclinical Studies for
hESC-Based Therapeutics
Final Product What is the Product Designed to
Do? What is the Target Site for Activity? Final
Product Production Scale Does Scale Effect
Composition? Formulation Cryopreserved
Format? Selective Cell Survival? Clinical
Administration Site of Administration? Effects
on Performance and Potential Adverse Events? Need
for Immunosuppression? Dose Required?
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Pharmacology Studies
What Is the Activity of the Cells?

• In Vitro Activity
• Protein and Gene Expression
• Factor Production
• Structural/ Metabolic Activity
• In Vivo Survival
• Survive Delivery
• Immune Responses
• Phenotype
• In Vitro and In Vivo
• Maturation Over Time
• Proliferative Capacity
• Activity in Disease Models
• Clinical Efficacy
• Histological Efficacy
• Dose
• Human Equivalent Dose
• Delivery Site and Volume
• Timing of Treatment

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Where Do The Cells Go?
Safety and Efficacy Implications

• Sensitivity of Assay
• Site for Intended Activity
• Sufficient Cells at Site
• Distribution Outside Target Site
• Migration at Local Site
• Over Extended Time

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Toxicology Studies
GRNOPC1

• Toxicity of Delivery
• Animal Survival
• Clinical Observations
• Systemic Toxicity
• Hematological
• Coagulation Parameters
• Clinical Chemistries
• Macropathology
• Micropathology
• Allodynia

Toxicity of Delivery
Considerations

• Doses of Product
• Tox Model
• Feasibility of Model
• Duration of Studies
• Duration of Human Cell Survival

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Tumorigenicity Studies
Challenges

• Human Dose
• Long-Term Cell Survival
• Large Numbers of Animals
• Mimic Human Setting
• Large Animals?
• Homologous ESC Systems?

• Teratomas
• Ectopic Tissues
• Local Injection Site
• Distal Sites

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Tumorigenicity Studies Lessons Learned
GRNOPC1 Deliberately Spiked with hESCs
Important Factors In Teratoma Formation

• hESCs Cell Number
• Site of Implantation
• Cell Aggregation State

2 x 106 Cells Intraspinal Cord Injection Assessmen
t 12 mos.
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Allogenicity Studies

• Immunosuppression Required?
• Duration of Immunosuppression?

Approaches
Challenges

• Allogenicity In Vitro
• Inflammatory Site
• Remove Immunosuppression?
• Monitor Engraftment?
• Monitor Rejection?
• Effects of Rejection

• hESC-Based Products are Xenografts in All Animal
  Models
• Allogenicity of Maturing Cells In Vivo
• Humanized Models Challenging
• In Vitro Analyses

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Cell Delivery in the Clinic
Considerations

• Local Delivery
• Delivery Site
• Intraoperative Delivery
• Rate of Delivery
• Skill Set Required for Delivery
• Effect of Delivery Device on Cells
• Training

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Design of Clinical TrialsKey Consideration
Patient Safety

• Protocol
• Delivery
• Logistics of Trial
• Minimize Potential Risks
• Balance Risk with Potential Efficacy
• Define Adverse Events
• Monitor for Adverse Events
• Monitor Cell Survival
• Assess Outcome Measures
• Short and Long-Term Follow-up

Interactions with

• Steering Committee
• DMC
• Outcomes Committee
• Neurosurgeons
• Radiologists
• Investigators
• ESCRO Committee

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Phase 1 Multi-Center Trial

• Open Label Trial
• Subacute, Functionally Complete T3-T12 Lesions
• Transplant 7-14 Days Post Injury
• Temporary Immunosuppression
• Primary Endpoints Safety Assessments
• Secondary Endpoints Multiple Outcome
  Measurements
• Frequent Short and Long-Term MRIs
• Immunological Monitoring

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Conclusions

• Numerous Considerations in Developing Cell
  Therapies
• Some Questions Common To All Cell Therapies
• Some Questions More Specific to hESC-Based
  Therapies
• Specific Nonclinical Study Designs Based on
  Clinical Considerations
• Clinical Trial Designs Require Interdisciplinary
  Input
• Frequent Monitoring Required