Three-Year Follow-Up of Delandistrogene Moxeparvovec in Duchenne Muscular Dystrophy: Long-Term Phase 3 EMBARK Trial Results

INTRODUCTION: Delandistrogene moxeparvovec, an adeno-associated virus vector-based gene therapy, delivers an optimized micro-dystrophin transgene to address dystrophin deficiency in Duchenne muscular dystrophy (DMD). EMBARK was a phase 3, randomized, double-blind, placebo-controlled, two-part crossover study evaluating the safety and effectiveness of delandistrogene moxeparvovec in patients with DMD who are ambulatory aged ≥ 4 to < 8 years. After completion of the EMBARK study at 2 years, patients had the option to enroll into the long-term follow-up open-label EXPEDITION study. METHODS: vg/kg; n = 64) were compared with a matched propensity score weighted external control (EC) cohort (n = 143) derived from randomized controlled clinical trials (patients treated with placebo only) and natural history datasets. Mixed-effects models for repeated measures accounted for missing data and estimated changes from baseline and between-cohort differences. All P values are nominal. RESULTS: At 3 years post-infusion, patients treated in part 1 of EMBARK (aged 7-10 years at 3 years) suggested sustained and statistically significant differences versus the matched EC cohort in change from baseline in North Star Ambulatory Assessment total score (between-cohort least-squares mean difference, 4.39 points; P = 0.0002), Time to Rise (- 6.05 s; P < 0.0001), and 10-m Walk/Run (- 2.70 s; P = 0.0039), suggesting durable slowing of disease progression. No new safety signals were identified through year 3, with no emerging cardiac safety concerns as the left ventricular ejection fraction remained above the normal threshold of 55% in this population over 3 years. There were no treatment-related deaths or discontinuations due to adverse events during follow-up. CONCLUSIONS: The 3-year follow-up of patients with DMD who are ambulatory treated in EMBARK part 1 compared with external comparators suggests durable functional benefit and a consistent safety profile following treatment with delandistrogene moxeparvovec, which may indicate long-term disease trajectory modification and increasing divergence from natural history over time. Graphical abstract available for this article. CLINICAL TRIAL NUMBERS: EMBARK: NCT05096221; EXPEDITION: NCT05967351.