Safety and efficacy of delandistrogene moxeparvovec versus placebo in Duchenne muscular dystrophy (EMBARK): Pivotal Phase 3 Primary results

Topic:

Clinical Trials

Poster Number: M164

Author(s):

Jerry Mendell, MD, Center for Gene Therapy, Nationwide Children’s Hospital, Francesco Muntoni, FRCPCH, FMedSci, University College London, National Institute for Health Research Great Ormond Street Hospital, Craig McDonald, MD, UC Davis Health, Eugenio Maria Mercuri, MD, PhD, POLICLINICO UNIV A. GEMELLI - DIV NEUROPSICHIATRIA INFANTILE, Emma Ciafaloni, MD, University of Rochester Medical Center, Hirofumi Komaki, MD, PhD, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan, Carmen Leon, MD, U of Florida, Andrés Nascimento, MD, Neuromuscular Unit, Neuropaediatrics Department, Hospital Sant Joan de Déu, Crystal Proud, MD, Children’s Hospital of the King’s Daughters, Ulrike Schara-Schmidt, MD, Universitaetsklinikum Essen, Aravindhan Veerapandiyan, MD, Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, Craig Zaidman, MD, Washington University in St. Louis School of Medicine, Maitea Guridi, PhD, F. Hoffmann-La Roche Ltd, Alexander Murphy, MD, PhD, Roche Products Ltd, Carol Reid, PhD, Roche Products Ltd, Christoph Wandel, F. Hoffmann-La Roche Ltd, Damon Asher, PhD, Sarepta Therapeutics, Eddie Darton, MD, [email protected], Stefanie Mason, Sarepta Therapeutics, Rachel Potter, PhD, Sarepta Therapeutics, Teji Singh, MD, Sarepta Therapeutics, Inc., Wenfei Zhang, PhD, Sarepta Therapeutics, Inc., Paulo Fontoura, MD, PhD, FAAN, F. Hoffmann-La Roche Ltd, Jake Elkins, MD, Sarepta Therapeutics, Louise Rodino-Klapac, PhD, Sarepta Therapeutics

Background and Objective: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations. Delandistrogene moxeparvovec is an adeno-associated viral vector-based gene transfer therapy, designed to compensate for absent functional dystrophin in DMD by delivering a transgene encoding engineered micro-dystrophin, which retains key functional wild-type dystrophin domains. As of September 2023, delandistrogene moxeparvovec is approved in the US, UAE and Qatar for the treatment of ambulatory pediatric patients aged 4 through 5 years with DMD with a confirmed DMD gene mutation. We report findings from Part 1 (52 weeks) of the two-part EMBARK trial (NCT05096221).

Methods: Key inclusion criteria: Ambulatory patients aged ≥4-<8 years with a confirmed DMD mutation within exons 18─79 (inclusive); North Star Ambulatory Assessment (NSAA) score >16 and <29 at screening; rAAVrh74 antibody titers <1:400; stable daily dose of oral corticosteroids for ≥12 weeks pre-screening. Eligible patients were randomized 1:1 to intravenous delandistrogene moxeparvovec (1.33×1014 vg/kg) or placebo. The primary endpoint was change from baseline in NSAA total score to Week 52. Results: At Week 52 (n=125), the primary endpoint did not reach statistical significance, although there was a nominal difference in change from baseline in NSAA total score in the delandistrogene moxeparvovec (2.6, n=63) versus placebo groups (1.9, n=61). Key secondary endpoints (time to rise, micro-dystrophin expression, 10-meter walk/run) demonstrated treatment benefit in both age groups (4-5 and 6-7 years; p<0.05); stride velocity 95th centile and time to ascend 4-steps showed benefit that was similar in magnitude and significant in the overall population (p<0.05).There were no new safety signals, reinforcing the favorable and manageable safety profile observed to date. Conclusions: Based on the totality of functional assessments including the timed function tests, treatment with delandistrogene moxeparvovec indicates beneficial modification of disease trajectory. Funded by Sarepta Therapeutics and F. Hoffmann-La Roche Ltd.