Long-term functional outcomes, safety, and micro-dystrophin expression following delandistrogene moxeparvovec treatment in DMD: EMBARK 2-year results

Topic:

Clinical Trials

Poster Number: P169

Author(s):

Jerry Mendell, [email protected], Sarepta Therapeutics, Inc., Cambridge, MA, USA, Dr. Francesco Muntoni MD,Dubowitz Neuromuscular Centre, London, UK, Prof Craig M. McDonald M.D., UC Davis Health, Sacramento, CA, USA, Dr Eugenio M. Mercuri MD, PhD Pediatric Neurology Institute, Catholic University and Nemo Pediatrico, Rome, Italy, Prof Emma Ciafaloni MD, University of Rochester Medical Center, Rochester, NY, USA, Dr Hirofumi Komaki MD, PhD, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan Carmen Leon-Astudillo MD Department of Pediatrics, University of Florida, Gainesville, FL, USA, Andrés Nascimento MD,Hospital Sant Joan de Déu, Fundacion Sant Joan de Déu, CIBERER – ISC III, Barcelona, Spain Crystal Proud Children’s Hospital of the King’s Daughters, Norfolk, VA, USA, Ulrike Schara-Schmidt MD, Department of Pediatric Neurology, University of Duisburg-Essen, Essen, Germany, Aravindhan Veerapandiyan MD, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, AR, USA, Craig M. Zaidman, Department of Neurology, Washington University in St Louis, St Louis, MO, USA, Matthew Furgerson, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Kai Ding Sarepta Therapeutics, Inc., Cambridge, MA, USA, Preeti Singh, Sarepta Therapeutics, Inc., Cambridge, MA, USA Rachael Potter PhD Sarepta Therapeutics, Inc., Cambridge, MA, USA, Damon R. Asher PhD, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Alexander P. Murphy MBChB PhD, Roche Products Ltd, Welwyn Garden City, UK ,Carol Reid Roche Products Ltd, Welwyn Garden City, UK, Gregory Hooper, Roche Products Ltd, Welwyn Garden City, UK, Carmen O. Torre, Roche Products Ltd, Welwyn Garden City, UK, Marianna Manfrini MD, PhD, F. Hoffmann-La Roche Ltd, Basel, Switzerland Jacob S. Elkins, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Louise R. Rodino-Klapac, Sarepta Therapeutics, Inc., Cambridge, MA, USA

Background: Delandistrogene moxeparvovec (rAAVrh74 vector-based gene therapy approved in the US and other select countries) delivers a transgene encoding micro-dystrophin, an engineered, functional form of dystrophin that stabilizes or slows Duchenne muscular dystrophy (DMD) progression. EMBARK (NCT05096221), a Phase 3, randomized, double-blind, placebo-controlled, two-part study, assesses delandistrogene moxeparvovec in DMD.

Methods: EMBARK enrolled ambulatory males with DMD aged ≥4─<8 years (Mendell. Nat Med. 2024). In Part 1 (52 weeks), patients received delandistrogene moxeparvovec (single intravenous dose 1.33×10^14 vg/kg) or placebo; in Part 2, patients crossed over. Muscle biopsies were performed at Weeks 12 and 64. Due to the crossover, 2-year functional outcomes from Part 1 delandistrogene moxeparvovec-treated patients were compared with external controls (EC), matched using prespecified propensity-score-weighted analyses based on baseline prognostic factors that impact DMD progression. Results: At 2 years, Part 1 delandistrogene moxeparvovec-treated patients (N=63) demonstrated statistically significant and clinically meaningful functional benefit versus EC (N=113–115, per functional assessment). Mean change from baseline: North Star Ambulatory Assessment total score, 2.63 versus –0.25 points (between-group difference: 2.88 points); Time to Rise, 0.65 versus 2.71 seconds (–2.06 seconds); 10-meter Walk/Run, –0.04 versus 1.32 seconds (–1.36 seconds); all P<0.01. Mean micro-dystrophin expression was sustained from Weeks 12 (n=17) to 64 (n=16) (34.29% vs. 45.68%; western blot). Between Weeks 52 and 104, 15 (23.8%) patients experienced 34 treatment-related treatment-emergent adverse events (AEs): troponin-I increase (6.3%); proteinuria, headache, gamma-glutamyl transferase increase, and nausea (3.2% each) the most frequent. One patient experienced two treatment-related serious AEs of rhabdomyolysis; both resolved. There were no deaths, discontinuations, or clinically significant complement-mediated AEs. Conclusions: 2-year results indicate favorable treatment effect of delandistrogene moxeparvovec on disease progression versus a well-matched EC. Stabilized functional outcomes, prognostic for delaying loss of ambulation, and sustained micro-dystrophin expression demonstrate durability of treatment. Safety was consistent with prior experience.