Two-Year Outcomes Following Delandistrogene Moxeparvovec Treatment in Ambulatory Patients with Duchenne Muscular Dystrophy: Phase 3 EMBARK Trial

Introduction: Delandistrogene moxeparvovec is a recombinant adeno-associated virus rhesus isolate serotype 74 vector-based gene therapy that addresses the absence of functional dystrophin in Duchenne muscular dystrophy (DMD). EMBARK is a phase 3, two-part, crossover, randomized, placebo-controlled trial assessing the safety and efficacy of delandistrogene moxeparvovec (single intravenous dose 1.33 × 10¹⁴ vector genomes/kg) in ambulatory male patients with DMD aged 4 to < 8 years; N = 125. One-year results demonstrated the manageable safety of delandistrogene moxeparvovec, consistent with previous clinical trials. The primary endpoint (change from baseline in North Star Ambulatory Assessment [NSAA] total score at 52 weeks compared with placebo) did not meet statistical significance. However, key secondary endpoints, comprising timed function tests, suggested slowing or stabilization of disease progression with delandistrogene moxeparvovec, which could become increasingly evident over longer periods of time. We report 2-year follow-up of safety and functional outcomes in patients receiving delandistrogene moxeparvovec in EMBARK part 1. Methods: As a result of the crossover study design, 2-year functional outcomes of patients receiving delandistrogene moxeparvovec in part 1 of EMBARK were compared, by pre-specified analysis, with a matched propensity score-weighted external control (EC). Results: At 2 years, EMBARK patients showed statistically significant benefit versus the EC cohort in functional outcomes prognostic for delaying loss of ambulation (NSAA, Time to Rise, 10-m Walk/Run), demonstrating sustained stabilization or slowing of disease progression. Delandistrogene moxeparvovec micro-dystrophin expression and sarcolemmal localization were maintained over 64 weeks. No new safety signals were observed between week 52 and week 104. Between baseline and week 104, there were no treatment-related deaths, study discontinuations due to adverse events, or clinically significant complement-mediated adverse events. Conclusions: At 2 years, stabilization or slowing of DMD disease progression was observed in ambulatory male patients with DMD aged 4 to < 8 years receiving delandistrogene moxeparvovec versus a matched EC cohort. Safety was consistent with EMBARK 1-year data and manageable with appropriate monitoring. ClinicalTrials.gov: NCT05096221.