for SCI: Challenges for Entry and Execution of Phase 1 Clinical Trials Challenges and Opportunities of Cellular Therapeutic Development

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1 Case Study: Human Embryonic Stem Cell Based Therapy for SCI: Challenges for Entry and Execution of Phase 1 Clinical Trials Jane S Lebkowski Ph.D NHLBI-PACT Workshop Sept 15, 2011 Challenges and Opportunities of Cellular Therapeutic Development CMC Unique Challenges New manufacturing platform Product characterization Formulation & distribution Unique Opportunities Generation of functional human cells with multifaceted MOAs Nonclinical Xenograft models Long term safety studies in disease or injury models Tissue regeneration Restoration of complex biological function Clinical Cell delivery Immunogenicity Clinical Trial Execution Outcomes Measures Path to Efficacy Population Potential to address previously intractable unmet medical needs 1

2 : Oligodendrocyte Progenitor Cells Cryopreserved Allogeneic Cell Population Derived from Human Embryonic Stem Cells Characterized Composition of Cells Contain Oligodendrocyte Progenitor Cells Produces Neurotrophic Factors Induces Myelination of Denuded Axons Intended Application Off-the-Shelf Product Spinal Cord Injury Other CNS Disorders Spinal Cord Injury: Pathology at the Lesion Postmortem human spinal cord with bony fracture, compression of cord (The Miami Project to Cure Paralysis 2004) No approved therapies No single conventional drug or biologic likely to impact the multiple mechanisms of degeneration 2

3 Challenge: Robust, Scalable Manufacturing Process and Product Characterization Production Process for hesc Cell Banks (Starting Material) hesc Cell Expansion hesc Differentiation to Harvest, Vialing and Cryopreservation rhbfgf rhtgfβ1 GFR Matrigel rhbfgf rhegf all-trans-retinoic Acid GFR Matrigel 3

4 Challenge: Controlled Production Process Characterization of Materials Starting Material Adventitious Agents Characterization of Unit Operations Cell Density Culture Format Timing of Induction Storage : Characterized Composition of Cells uhescs NSCs OPCs Neurons Astrocytes Marker A Oligodendrocytes mesoderm endoderm epithelial cells Marker D Marker E Marker F Marker B Multiple cell types may be important for function Single marker may not definitively identify a particular cell type Marker C 4

5 : Characterized Cellular Composition Characterized for Phenotypic Properties Associated with Multiple Cell Types Whole Genome MicroArray Analysis Quantitative RT-PCR Flow Cytometry High Content Imaging Biological Assays for Specific Cell Types Composition Correlated with In Vivo Activity in Animal Models Critical for Establishing Cell Composition Specifications Product Release NG-2 and Tra1-60 Expression in GMP Lot QC Testing Morphology Viability Cell composition OPC Phenotype Extraneous Phenotypes lo neg hi Morphology Undifferentiated hescs Adventitious Agent Testing Sterility and Mycoplasma Sterility and Mycoplasma Endotoxin neg lo 0.1 hi 0 NG-2 Tra1-60 5

6 Has Three Properties To Support CNS Repair Neurotrophic Factors Induces Axonal Sprouting Remyelination Revascularization Host Endothelial Cells Associated With Vessel Growth Produces Defined Neurotrophic Factors TGF-b2, HGF, BDNF, Activin A, Midkine Induces Revascularization at Lesion Site Remyelinates Denuded Axons Induces Myelin Wrapping Challenge for Mechanism of Action Studies and Potency Assays Challenge: Long, Large Nonclinical Studies to Evaluate Safety Xenograft Models Injury Models 6

7 Safety/Efficacy Profile of Activity/ Efficacy Biodistribution Dosing/Delivery Toxicity Tumorigenicity Ectopic Tissue Immune Rejection >26 Studies and >2000 Rodents Survives in the Spinal Cord Predominantly Neural Cells Types Improves Locomotor Activity Reduces Parenchymal Cavitation Migrates Through the Spinal Cord Does Not Increase Mortality Does Not Induce Allodynia Does Not Induce Systemic Toxicity Does Not Produce Teratomas Infrequent Ectopic Structures Observed Restricted to the Injury Site Not Highly Susceptible to Direct Immune Responses Delivery of : Elective Surgical Delivery Delivery 2x ul Injection 5mm Caudal of Injury Epicenter Injection Performed Using Syringe Positioning Device Support Frame Microdrive Syringe and Needle 7

8 SCHEMA SCI Phase 1 Study Schema Acute complete SCI SUBJECT Protocol CP35A007 Protocol CP35A008 MRI MRI MRI MRI MRI MRI MRI MRI MRI MRI Day -14 Day -11 Day -3 Day -2 Day -1 Day 1 Day 7 Day 30 Day 60 Day 90 Day 120 Day 180 Day Year 5 Years 15 Years screening baseline Day 0 Days Immunosuppression taper In person visits Phone f/u INJECTION Begin immunosupression Discontinue Immunosuppression Measures of Sensory and Motor Function Spinal Cord Independence Measure (SCIM) International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) 30, 60, 90, 120, 180, 270 and 365 U of Alabama Index of Motor Recovery (UAB-IMR) International Spinal Cord Injury Pain Basic Data Set International Spinal Cord Injury Bowel and Bladder Data Set Challenge: Clinical Trial Execution Initial Restrictive ti Inclusion/Exclusion l i Criteria i Multiple Clinical Trial Sites Numerous Committee Approvals Outcome Measures for Novel Indications Rigorous Follow-up Staged Expansion of Inclusion Criteria totarget Efficacy Population 8

9 : Thoracic Cohort Safety Data Gating for Clinical Development Plan in Spinal Cord Injury Complete Thoracic Dose Escalation Cohorts Complete Thoracic Low Dose Cohort Complete Cervical Dose Escalation Cohorts Incomplete Thoracic Injury Cohorts Incomplete Cervical Injury Cohorts Challenges and Opportunities of Cellular Therapeutic Development CMC Unique Challenges New manufacturing platform Product characterization Formulation & distribution Unique Opportunities Generation of functional human cells with multifaceted MOAs Nonclinical Xenograft models Long term safety studies in disease or injury models Tissue regeneration Restoration of complex biological function Clinical Cell delivery Immunogenicity Clinical Trial Execution Outcomes Measures Path to Efficacy Population Potential to address previously intractable unmet medical needs 9