The state stem cell agency

Tuesday, February 10, 2009 1

HESC-DERIVED CELL THERAPIES: SAFETY in TRANSLATION

Marie Csete MD, PhDChief Scientific Officer

California Institute for Regenerative Medicine

June 26 & 27, 2008 2

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TIME TO COLLECTIVELY CATCH OUR BREATH

-FDA HEARING APRIL 2008

-SAFETY OF HESC DERIVATIVES:MAJOR CONCERNS

-CIRM IS INITIATINGDISEASE TEAMS 2009WITH IND APPLICATIONAS 4 YEAR MILESTONE

-EARLY TRANSLATION:BOTTLENECKS

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SAFETY is #1

Historical precedent: Gene therapy• Acute procedure (surgical) risks

– Pain should be more of a consideration• Transmitted disease from donor• Xenogeneic contamination• Rejection• Survival (non-immune mediated death)• Tumorigenicity• Unintended consequences

– Fusion, transdifferentiation poorly understood

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Transmitted disease from donor:Should be controllable

INFECTIONEnormous precedents from FDA:

Blood banking and solid organ transplantationStandardized assays available

(HIV, CMV, HTLV, hepatitis, etc.)Plus…added time to analyze master banks

XENOGENEIC VIRUSES: Also established guidelines

ADDITIONAL TESTING—Cancer risk? Donor re-contact?

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Xenogeneic contaminants

• Routine for hESC growth & differentiation• All companies presenting at April FDA meeting

used non-human reagents in their product mfr• Scale-up with human excipients: $$$• Safety can be addressed: Individualized assays

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Allogeneic immune response

• Every cell type different• Differentiation-dependent immunogenicity• Pre-clinical studies should cover all stages of

differentiation• Rodent models (even primate models) not

predictive of human reaction• Immune privilege (CNS) is relative

– Long-term: Autologous survival in brain is superior• Monitoring by biopsy

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What is reasonable for an immunosuppression plan?

-- Pre-clinical exposure of cultured cells to drug--Conservative withdrawal of immunosuppression

-monitored (how?)-Phase I: Is the graft still there?

-- Transplant immunologist involvement-- Extensive data collection

-major and minor histocompatibility-allogeneic vs. autoreactive T cells-non-invasive assays from solid organ tx

--How can we capture the power of UNOS?

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Targeted research

OPTIMAL IMMUNOSUPPRESSANT DRUG?Unusual effects of drugs on undifferentiated cells

ALLOGENEIC REACTIONS TO CELL RX: UNPREDICTABLE– Differentiation state– Single cell vs. clusters– Heterogeneity of transplanted population/angiogenic properties– iPS cells don’t guarantee immune tolerance

TOLEROGENIC STRATEGIESFeb 4-5 CIRM Immunology Workshop

NON-INVASIVE MONITORING ASSAYS

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Tumorigenesis

• Major concern at April FDA hearing: Teratoma• Other proliferating cells as tumor sources?

– Placental/amniotic SC: Pluripotent but senesce (not 100%)

• Subtle chromosomal abnormalities• Particularly a problem for CNS applications• How long should animals be monitored?• Undifferentiated ESC à teratomas

– Reliance on differentiation protocol• Suicide genes? (Driven off Oct-4)• In theory: iPS have same issues

June 26 & 27, 2008 10

Right now: No guarantees

-Sorting techniques vs.-Differentiation protocols-(In)Sensitive imaging-Other non-invasive assays to monitor early tumor

formation-Cancer ßà stem cells

Basic science: Self-renewal, environment

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Other technical hurdles

• MIGRATION: All stem cells are migratoryHome to hypoxic sites

• SCALE-UP under GMP CONDITIONS– November 3 at CIRM

• POOR ANIMAL MODELS- Underestimate human disease heterogeneity, complexity- Incomplete vs. complete SC injury - No large animal model for traumatic injury?

• DRUG-CELL INTERACTIONS- Specific to target disease- P450 expression in undifferentiated stem cells

June 26 & 27, 2008 12

Trial design: Phase I/II

• Efficacy end-points ideally incorporated into Phase I• Becomes indirect monitor of graft survival• Can speed translation by years, if Phase I is well-

designed• Almost all applications require objective pain monitoring

– Our results showing decreased pain with mixed marrow tx vs. fusion with peripheral nerve and increased pain

– GABA, endothelins, ?channels• Quantitative end-points by trained domain experts

– Important quantitative end-points not monitored well in animals– Quantitative pain testing requires real expertise

June 26 & 27, 2008 13

What is the best first application for hESC-derived rx?

June 26 & 27, 2008 14

DISEASE TEAM PLANNING AWARDS(and other conversations)

Muscular dystrophiesALSSMAMSCancers (Brain, many others)Type I DiabetesAlzheimer’s diseaseESLDInherited metabolic disordersARDSMITraumatic injuries (spinal cord, craniofacial, burn)Senescence of various organ systems

June 26 & 27, 2008 15

Spectrum of opinion

• HYPERACUTE

• LIFE-SPAN LIMITED

• CHRONIC, INTOLERABLE

• ANTICIPATED COMPLICATIONS

RISKSAFETY

SAFETYRISK

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• Hyperacute disease– Unless new, compelling animal models emerge, not

easy to justify now. (What will we learn?)• Shortened life-span (ALS, DMD, SMA)

– Excellent historical controls (ALS)– Immunosuppression preferable to death– Patients don’t tolerate placebo-controlled trials

• Chronic, debilitating diseases– Higher safety standard– Dependent on current rx options

Each has distinct risk: benefit

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Learn from failure: DMD

• Human myoblasts won’t migrate any faster than mouse• How to target huge volume of muscle mass?

-Dog model studies essential• Anatomic vs. functional cure (strength) models well-

established, highly quantitative• Relative myogenicity of different myoblast progenitors

well-studied: New cell tools are available– HESC-derived– Mesangioblast– Satellite subpopulations

• Revisit failed clinical trials• Potential for palliation (and cure?)

– HOW TO TARGET RESPIRATORY MUSCLES?

June 26 & 27, 2008 19

ACTIVE PUSH TOWARD TRANSLATION

BASIC MECHANISMS OF CHROMOSOMAL STABILITY IN CULTUREBASIC MECHANISMS OF MIGRATIONNEW IMAGING TECHNOLOGIESBASIC IMMUNOLOGY RESEARCHNOVEL TOOLS FOR SORTING

NEW ANIMAL MODELS/HUMANIZED MODELS

SCALE-UP

SENSITIVE ASSAYS FOR TERATOMA FORMATIONSENSITIVE ASSAYS FOR REJECTION/STATE OF IMMUNE SYSTEMDEFINITION OF DISEASE MICROENVIRONMENTS

Plus…DISEASE TEAM EFFORT

June 26 & 27, 2008 20

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HurdlesàOpportunity

• Identify the real problems– Fund their solution

• Identify non-problems– Work with regulatory agencies (using all our allies) to

prevent focus on trivial issues• Leadership

– Our vantage point is broad enough that we can see the big picture landscape

– Partnering increases the view: Canada, Australia, JDRF, UK; others in negotiation

– Open discourse with regulatory agencies on risk vs. benefit

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• Terminal differentiation from hESC is harder than anticipated– Rely on in vivo differentiation in a hostile environment?– Inability to define the ‘final’ cell product

• Despite large resources we can’t go it alone

• hESC-derived therapies necessary for some diseases

• Patients are impatient for progress and have distinct ideas about safety

• The ‘country’ of stem cell researchers is divided– APRIL FDA RULING IS A SIGNAL THAT HESC-DERIVED

THERAPIES ARE FAR AWAY vs. UNPRECENDENTED INSIGHT INTO COMMON PROBLEMS THAT DESERVE RESEARCH FOCUS

– Glass is half-full

MAJOR INSIGHTS

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Adult stem cells vs. ESC

MSCs being globally applied– Already reaching the clinic for bone defects– Cardiac applications: No Phase III yet– GVHD IV: Usually fatal– Transient responses in all cases when given into

circulation (re-dosing required)– Immunologic implications of re-dosing– Not strictly regenerative therapies

2/10/2009 24

Pipeline encompasses all the hurdles(with some targeted RFAs)

Approved IND

Disease Team

Tools & Technol

Training Grants

SEED

Comprehensive

New Faculty I, II

New Cell Lines

Bridges to Stem Cell Research

Innovation Awards

Development Candidate

Translational Research I

Preclinical hurdles Clinical Research

Laying theFoundation

Scheduled RFAsUpcoming RFAs

Basic biology