Long-Term Functional Outcomes, Safety, and Micro-Dystrophin Expression Following Delandistrogene Moxeparvovec Treatment in DMD: EMBARK 2-Year Results

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Background/Purpose: Delandistrogene moxeparvovec (rAAVrh74 vector-based gene therapy approved in the United States and other select countries) delivers a transgene encoding micro-dystrophin, an engineered, functional form of dystrophin that stabilizes/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 to <8 years. In Part (P) 1 (52 weeks), patients received delandistrogene moxeparvovec (single intravenous dose 1.33×10 14 vg/kg) or placebo. In P2, patients crossed over. Muscle biopsies were performed at weeks 12 and 64. Due to crossover, 2-year functional outcomes from P1-treated patients were compared with external controls (EC), matched using propensity-score-weighted analyses of baseline (BLN) prognostic factors of DMD progression. Results: At 2 years, P1-treated patients ( n = 63) demonstrated statistically significant and clinically meaningful functional benefit versus EC ( n = 113–115, per assessment). Mean change from BLN (between-group difference): North Star Ambulatory assessment total score, 2.63 versus −0.25 points (2.88 points); Time to Rise, 0.65 versus 2.71 seconds (−2.06 seconds); 10-m 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 week 64 ( n = 16; 34.29% versus 45.68%; western blot). Between week 52 and 104, 15 (23.8%) patients had 34 treatment-related (TR) treatment-emergent adverse events (AEs), including troponin-I increase (6.3%), proteinuria, and headache (3.2% each). One patient had two serious TRAEs of rhabdomyolysis; both resolved. Between BLN and W104, there were no TR deaths, study discontinuations due to AEs, or clinically significant complement-mediated AEs. Conclusion: Two-year results indicate a favorable and durable effect of delandistrogene moxeparvovec on disease progression versus a well-matched EC. Safety was consistent with prior experience and manageable with appropriate monitoring. Publication History Article published online: 26 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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