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

1. Outcomes: MDA-NINDS Workshop on Best Practices for Gene Therapy Programs (April 2014)(…and NINDS’ Adaptations)John D. Porter, Ph.D.Program DirectorNational Institute of Neurological Disorders and StrokeNational Institutes of HealthMSG Conference: 9/22/2014

2. 2Gene 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?

3. Workshop ChargeIdentify key challenges in gene therapy development for neuromuscular diseases & the field in generalIdentify possible solutions & ways to mitigate challenges or risksImpact design and management of translational funding programs broadly (public & private funders)Organizers: Valerie Cwik, Amelie Gubitz, Jane Larkindale, John Porter, & Hao Wang

4. Workshop FormatThree Orienting Talks: Keynote (Kathy High; lessons from hemophilia & retinal diseases) Case study (Jim Wilson; lessons from EMA approval of Glybera) FDA-CBER didactic presentation (Wilson Bryan; regulatory landscape) Panels:Establishing Adequate Scientific Premise for Clinical Trials in Gene Therapy Addressing Regulatory Process IssuesIntellectual Property & Commercialization of Gene TherapiesDifference: focus on broad lessons, not on advances from individual participant’s labs

5. Keynote & Session 1(Preclinical Premise)Optimize early & commit to candidate prior to IND-enabling studiesRigorous optimization for adequate level of effect—then commitKathy High: “Can let whole career go by while looking for the perfect vector” Many questions unanswerable until first-in-manToolsCREATE Program: Bio Discovery U01 optimize (vector, transgene, delivery)Bio Development UH2/UH3 (IND-enabling studies)

6. Courtesy Hao WangtR21IGNITE*PAR-14-286/287/288/289

7. IGNITE PreviewNew IGNITE R21sDevelopment of Translational Animal Models & Pharmacodynamic Measures Relevant to the Discovery of Therapeutics to Treat Neurological DiseasePharmacodynamics &/or In Vivo Efficacy Studies for Small Molecules & Biologics/Biotechnology ProductsAssay Development & Therapeutic Agent Identification & Characterization to Support Therapeutic Discovery

8. Session 2: Gene Therapy Trials in Pediatric PopulationsFDA OCTGT perspectiveChildren can’t provide consent and require extra protection; sponsors must provide evidence of possible direct benefitShould not rule out possibility that gene therapy interventions later in disease progression could still be effectivePI 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 inconsistentlyPediatric disease: Cellular target (muscle/neurons/etc.) may be too far diminished to allow later treatments to be effectiveGene therapy re-administration issue as children grow (indication-specific)

9. Example—Nationwide Children’s SMA Program Advocacy-funded gene therapy trial in SMA type 1 infants has been initiated: systemic delivery of AAV9-SMNNINDS 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

10. Use the appropriate animal model/species for the purposeMercedes Serabian, FDA: “Models don’t predict, they inform”Efficacy/biodistribution/immune response/toxicologyEfficacy: 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 tropismImmune response/tox: ? translatability from animals to humans (but need data to interpret animal efficacy & safety)ToolsNINDS IGNITE tR21s and Rigor Guidance

11. Start with a Target Product Profile (TPP)Consider at the beginning what you’ll need at the endAt preclinical stage, need to have an idea how phase 1-3 clinical trials might lookTPP facilitates an efficient dialogue between FDA and sponsorToolsCREATE Bio applications need to define TPP and initial clinical POC

12. Data should be kept in public domain whenever possibleSome journals now publish data relevant to the regulatory review and commercial developmentWhen pre-clinical papers focus on pharmacology/toxicity/bio-distribution, may support cross-referencing products within the same technology platform National Gene Vector Biorepository (NGVR) databaseTransparency: Include pertinent experimental details—journals: expanded methods sections, rigor criteria

13. Take-homes from Glybera Case Study & Session 2 (Regulatory Process)Natural history data critical—Tools: RDCRNs, R01s and PAGsDefine 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 activityEstablish adequate scientific rationale to justify risk, especially for pediatric cohort—Tools: entry and review criterion of CREATE Bio Discovery TrackTake advantage of early and regular meetings with FDA/OCTGT—Tools: integrated into CREATE awards; NINDS MOA with FDA/CBER

14. Take-homes from Session 3 (IP and Commercialization)IPIP 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 malariaSupreme Court Myriad Genetics, Inc. decision: isolated genes are no longer patentable (June 2013)ToolsCREATE FOAs include section on IP with appropriate guidance

15. CommercializationForbes April 2014 article “Gene Therapy’s Big Comeback”; venture capital and public markets are re-entering the field; since 2013, investment > $600 MPrivate 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 profitableToolsCREATE FOAs include section on commercialization with appropriate guidance

16. Planned publication from MDA-NINDS WorkshopGuidance from new revisions of NINDS translational programs & new NINDS staff with industry experienceEasier handoffs between NINDS OTR & OCRRigor is the buzz word—will go NIH-wideAppearance of internal Morbidity & Mortality Conferences at NINDS (lessons learned from what’s lost or found in translation)Next Steps

17. AcknowledgementsWorkshop ParticipantsWorkshop Co-OrganizersValerie CwikAmelie GubitzJane LarkindaleHao Wang Paul MuhlradMDA & NINDS support