Advances in Gene Therapy Programs and Best Practices Workshop Insights
Workshop outcomes and discussions from the MDA-NINDS Workshop on Best Practices for Gene Therapy Programs, highlighting key challenges, possible solutions, and the impact on translational funding programs. The workshop format included orienting talks and panels focusing on scientific premise, regulatory issues, and commercialization of gene therapies. Keynote speakers emphasized the importance of early optimization in preclinical studies for successful gene therapy development.
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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 Stroke National Institutes of Health MSG Conference: 9/22/2014
Gene Therapys Time? Resources & Science?, Yes; but, Have We Learned? Forbes 3/26/2014 Gene Therapy's Big Comeback ($618M VCs, IPOs) Gene Therapy's Second Act A decade and a half after a series of tragic setbacks led to critical reevaluations, scientists say gene therapy is ready to enter the clinic Scientific American Volume 310, Issue 3 2
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: 1. Establishing Adequate Scientific Premise for Clinical Trials in Gene Therapy 2. Addressing Regulatory Process Issues 3. 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 studies Rigorous 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)
* tR21 IGNITE PAR-14-286/287/288/289 Courtesy Hao Wang
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)
ExampleNationwide Childrens 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 purpose Mercedes 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) Tools NINDS 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
Next Steps 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)
Acknowledgements Workshop Participants Workshop Co-Organizers Valerie Cwik Amelie Gubitz Jane Larkindale Hao Wang Paul Muhlrad MDA & NINDS support
