A Randomized, Double-Blind, Placebo-Controlled, Gene-Delivery Clinical Trial of rAAVrh74.MHCK7.micro-dystrophin for Duchenne Muscular Dystrophy

Topic:

Clinical Trials

Poster Number: 49

Author(s):

Jerry R. Mendell , Perry Shieh MD, PhD, Zarife Sahenk , Kelly J. Lehman , Linda P. Lowes , Natalie F. Miller DPT, Megan A. Iammarino DPT, Lindsay N. Alfano DPT, Jeremy D. Woods , Christy L. Skura , Howard C. Mao , Loretta A. Staudt PT,MS, Rachael A. Potter , Danielle A. Griffin , Sarah Lewis , Larry Hu , Sameer Upadhyay , Teji Singh , Louise R. Rodino-Klapac PhD

Institutions:

1. Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, 2. University of California, Los Angeles, 3. The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA, 4. Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, 5. Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, 6. Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, 7. Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, 8. The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, USA;, 9. Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA, 10. Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA, 11. Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA, 12. Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA, 13. Sarepta Therapeutics, Inc., Cambridge, MA, USA, 14. Sarepta Therapeutics, Inc., Cambridge, MA, USA, 15. Sarepta Therapeutics, Inc., Cambridge, MA, USA, 16. Sarepta Therapeutics, Inc., Cambridge, MA, USA, 17. Sarepta Therapeutics Inc, Cambridge, Massachusetts, USA, 18. Sarepta Therapeutics, Inc., Cambridge, MA, USA, 19. Sarepta Therapeutics, Inc., Cambridge, MA, USA

Background: Adeno-associated virus (AAV)-mediated gene transfer therapy has shown early signs of potential to treat Duchenne Muscular Dystrophy (DMD). The intent of rAAVrh74.MHCK7.micro-dystrophin (SRP-9001) is to safely express a functional micro-dystrophin protein in skeletal and cardiac muscle. Preclinical studies and Phase 1b/2 clinical trial findings warrant further investigation of gene transfer therapy in DMD.

We designed an AAV vector (rAAVrh74) containing a codon-optimized human micro-dystrophin transgene driven by a muscle-specific promoter with a cardiac enhancer, MHCK7, to be tested in a 3-part Phase 2 clinical trial that included two 48-week randomized, double-blind, placebo-controlled periods (Part 1 and 2) and an up-to-212-week open-label follow-up period (Part 3). Key eligibility criteria included ambulatory boys aged ≥4 to <8 years with a confirmed DMD gene mutation (exons 18–58), an established clinical diagnosis and stable steroid dosing (≥12 weeks). A single-dose (2×1014 vg/kg) SRP-9001 intravenous (IV) infusion treatment arm was compared with a placebo IV infusion arm. Safety endpoints included incidence of serious adverse events and treatment-emergent adverse events (up to Week 260). Primary efficacy endpoints included change in micro-dystrophin expression (baseline to Week 12) and change in functional outcomes by North Star Ambulatory Assessment (baseline to Week 48). Secondary endpoints included Time to Rise, 4-Stair Climb, and 10-Meter and 100-Meter Timed Tests (baseline to Week 48).

Objectives: The purpose of this study is to evaluate the safety and efficacy of IV SRP-9001 in people with DMD by measuring biological and clinical endpoints in a Phase 2 multicenter, randomized, double-blind, placebo-controlled trial (NCT03769116).

Results: Results from the 41 patients that have been randomized and dosed (SRP-9001 or placebo) in Part 1 will be presented.

Conclusions: Initial safety and efficacy findings from this study suggest the potential of SRP-9001 therapy for clinically meaningful functional improvements in people with DMD.

This study was funded by Sarepta Therapeutics, Inc.