Outcomes: MDA-NINDS Workshop on Best Practices for Gene Therapy Programs (April 2014)

(…and NINDS’ Adaptations)

John D. Porter, Ph.D.Program Director

National Institute of Neurological Disorders and StrokeNational Institutes of Health

MSG Conference: 9/22/2014

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Gene Therapy's Second ActA decade and a half after a series of tragic setbacks led to critical reevaluations, scientists say gene therapy is ready to enter the clinicScientific American Volume 310, Issue 3

Forbes 3/26/2014 Gene Therapy's BigComeback ($618M VCs, IPOs)

Gene Therapy’s Time?

Resources & Science?, Yes;but, Have We Learned?

Workshop Charge

Identify key challenges in gene therapy development for neuromuscular diseases & the field in general

Identify possible solutions & ways to mitigate challenges or risks

Impact design and management of translational funding programs broadly (public & private funders)

Organizers: Valerie Cwik, Amelie Gubitz, Jane Larkindale, John Porter, & Hao Wang

Workshop Format

Three Orienting Talks: 1. Keynote (Kathy High; lessons from hemophilia & retinal diseases) 2. Case study (Jim Wilson; lessons from EMA approval of Glybera) 3. FDA-CBER didactic presentation (Wilson Bryan; regulatory landscape)

Panels:4. Establishing Adequate Scientific Premise for Clinical Trials in Gene

Therapy 5. Addressing Regulatory Process Issues6. Intellectual Property & Commercialization of Gene Therapies

Difference: focus on broad lessons, not on advances from individual participant’s labs

Keynote & Session 1(Preclinical Premise)

Optimize early & commit to candidate prior to IND-enabling studiesRigorous optimization for adequate level of effect—then commit

Kathy High: “Can let whole career go by while looking for the perfect vector” Many questions unanswerable until first-in-man

Tools• CREATE Program: • Bio Discovery U01 optimize (vector, transgene, delivery)• Bio Development UH2/UH3 (IND-enabling studies)

Courtesy Hao Wang

tR21IGNITE

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PAR-14-286/287/288/289

IGNITE Preview

• New IGNITE R21s– Development of Translational Animal Models &

Pharmacodynamic Measures Relevant to the Discovery of Therapeutics to Treat Neurological Disease

– Pharmacodynamics &/or In Vivo Efficacy Studies for Small Molecules & Biologics/Biotechnology Products

– Assay Development & Therapeutic Agent Identification & Characterization to Support Therapeutic Discovery

Session 2: Gene Therapy Trials in Pediatric Populations

FDA OCTGT perspective• Children can’t provide consent and require extra protection; sponsors must

provide evidence of possible direct benefit• Should not rule out possibility that gene therapy interventions later in disease

progression could still be effective

PI perspective (industry and academia)• Need for equipoise between right to safety & right to treatment • JAMA (2005): “Quantifying the Federal Minimal Risk Standard—Implications for

Pediatric Research Without a Prospect of Direct Benefit”; problem: IRBs interpret risk standards inconsistently

• Pediatric disease: Cellular target (muscle/neurons/etc.) may be too far diminished to allow later treatments to be effective

• Gene therapy re-administration issue as children grow (indication-specific)

Example—Nationwide Children’s SMA Program • Advocacy-funded gene therapy trial in SMA type 1 infants has

been initiated: systemic delivery of AAV9-SMN• NINDS is funding tU01 for intrathecal delivery of AAV9-SMN

(SMA type 2/3); with Cure SMA as partner

Evident that FDA will approve pediatric gene therapy trials under specific circumstances;

Need harmonization between EMA and FDA

Use the appropriate animal model/species for the purposeMercedes Serabian, FDA: “Models don’t predict, they inform”Efficacy/biodistribution/immune response/toxicology• Efficacy: rigorous design; target ‘feasibility;’ importance of

magnitude of effect (reduction in efficacy in humans is expected); use of host species sequence in animal efficacy

• Biodistribution: large animal species; species-dependence in vector tropism

• Immune response/tox: ? translatability from animals to humans (but need data to interpret animal efficacy & safety)

ToolsNINDS IGNITE tR21s and Rigor Guidance

Start with a Target Product Profile (TPP)• Consider at the beginning what you’ll need at the end• At preclinical stage, need to have an idea how phase 1-3 clinical

trials might look• TPP facilitates an efficient dialogue between FDA and sponsor

Tools• CREATE Bio applications need to define TPP and initial clinical

POC

Data should be kept in public domain whenever possible• Some journals now publish data relevant to the

regulatory review and commercial development• When pre-clinical papers focus on

pharmacology/toxicity/bio-distribution, may support cross-referencing products within the same technology platform

• National Gene Vector Biorepository (NGVR) database• Transparency: Include pertinent experimental details—

journals: expanded methods sections, rigor criteria

Take-homes from Glybera Case Study & Session 2 (Regulatory Process)

• Natural history data critical—Tools: RDCRNs, R01s and PAGs

• Define primary efficacy endpoint & biomarkers—Tools: CREATE requires TPP & enables target engagement marker development

• Determine manufacturing process early—Tools: process development/scale-up is a CREATE Bio Discovery Track activity

• Establish adequate scientific rationale to justify risk, especially for pediatric cohort—Tools: entry and review criterion of CREATE Bio Discovery Track

• Take advantage of early and regular meetings with FDA/OCTGT—Tools: integrated into CREATE awards; NINDS MOA with FDA/CBER

Take-homes from Session 3 (IP and Commercialization)

IP• IP surrounding gene therapy products is complex (“IP in gene therapy is

scattered, stale and untested in court”)• IP can be regarded as a friend or foe; a space to pay attention to (note: most

patents in gene therapy field are held by academic institutions, not the for-profit sector)

• Community should develop pre-competitive space to enable early, exploratory research; example: industry consortium sharing IP for malaria

• Supreme Court Myriad Genetics, Inc. decision: isolated genes are no longer patentable (June 2013)

Tools• CREATE FOAs include section on IP with appropriate guidance

Commercialization• Forbes April 2014 article “Gene Therapy’s Big Comeback”; venture

capital and public markets are re-entering the field; since 2013, investment > $600 M

• Private sector expected to focus on “low hanging fruit”; federal/non-for-profit funding still needed for challenging indications (e.g., neuromuscular diseases)

• Reality check: gene therapies for ultra-rare diseases will likely never be profitable

Tools• CREATE FOAs include section on commercialization with appropriate

guidance

• Planned publication from MDA-NINDS Workshop• Guidance from new revisions of NINDS

translational programs & new NINDS staff with industry experience

• Easier handoffs between NINDS OTR & OCR• Rigor is the buzz word—will go NIH-wide• Appearance of internal Morbidity & Mortality

Conferences at NINDS (lessons learned from what’s lost or found in translation)

Next Steps

Acknowledgements

• Workshop Participants• Workshop Co-Organizers– Valerie Cwik– Amelie Gubitz– Jane Larkindale– Hao Wang

• Paul Muhlrad• MDA & NINDS support