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 Therapy’s 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 INDenabling 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)
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
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 forprofit 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/nonfor-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