As of 2025, approximately 160 clinical trials targeting Duchenne muscular dystrophy (DMD) are ongoing or pending. These trials explore a range of therapeutic strategies, including gene therapies, exon-skipping approaches, and other innovative treatments. Among the most high-profile developments is Elevidys (delandistrogene moxeparvovec), a recombinant AAV-based gene therapy. Elevidys has received regulatory approval in several countries.
One of the most significant trials aimed at supporting the development of Elevidys is the EMBARK trial, a global Phase 3, randomized, double-blind, placebo-controlled study, which results were published at the end of 2024 [1]. It evaluated the safety and efficacy of a single intravenous dose of delandistrogene moxeparvovec in ambulatory boys aged 4 to 7 years with confirmed DMD (n = 63) or placebo (n = 62). The therapy delivers a shortened but functional version of the dystrophin gene (micro-dystrophin) to muscle cells. The primary trial endpoint was an improvement in North Star Ambulatory Assessment (NSAA) score at Week 52. NSAA is a 17-item functional scale developed in the UK. It assesses gross motor skills in ambulant boys with DMD, with each item scored on a 3-point scale (0–2) based on performance. In the EMBARK study after 52 weeks, this primary improvement at NSAA has not been met. However, some secondary endpoints favored treatment, though they also fell short of statistical significance. Notably, muscle biopsies confirmed robust microdystrophin expression, and the safety profile was manageable. In early 2025, Year 2 results from EMBARK trial were released [2]. Delandistrogene moxeparvovec -treated patients showed statistically significant and clinically meaningful functional benefit in NSAA total score and other scales, such as 10 Meter Walk Test. Two-year safety outcomes of EMBARK Part 1-treated patients were consistent with prior experience. Most treatment-emergent adverse events were reported within the first 90 days.
On March 2025, Sarepta announced that a patient treated with Elevidys had died from acute liver failure. [3]. This tragic incident is part of a broader concern over safety risks in gene therapy for DMD. An independent Data Monitoring Committee (DMC) reviewed the incident and concluded that the overall benefit-risk profile
remains favorable, recommending the continuation of the trials without changes to study protocols. A key challenge in DMD gene therapy may be the immune system’s response to dystrophin. As gene therapy opens new possibilities for DMD, maintaining a focus on patient safety and long-term results will be key to its continued success.
Key Points:
- EMBARK trial, a global Phase 3, randomized, double-blind, placebo-controlled study on delandistrogene moxeparvovec, an AAV based gene therapy, in a single intravenous dose of delandistrogene moxeparvovec in ambulatory boys aged 4 to 7 years with confirmed DMD diagnosis.
- EMBARK trial results at 52 weeks were published at the end of 2024. The primary endpoint (improvement in the NSAA score) was not met, however secondary endpoints showed some benefits.
- In early 2025, Year 2 results from the EMBARK trial showed that delandistrogene moxeparvovec-treated patients had significant functional improvements in NSAA scores and the 10 MWT.
References:
- Mendell JR, Muntoni F, McDonald CM, Mercuri EM, Ciafaloni E, Komaki H, Leon- Astudillo C, Nascimento A, Proud C, Schara-Schmidt U, Veerapandiyan A, Zaidman CM, Guridi M, Murphy AP, Reid C, Wandel C, Asher DR, Darton E, Mason S, Potter RA, Singh T, Zhang W, Fontoura P, Elkins JS, Rodino-Klapac LR. AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial. Nat Med. 2025 Jan;31(1):332-341. doi: 10.1038/s41591-024-03304-z. Epub 2024 Oct 9. PMID: 39385046; PMCID: PMC11750718.
- Mendell J, Muntoni F, McDonald CM, et al. Long-term functional outcomes, safety, and micro-dystrophin expression following delandistrogene moxeparvovec treatment in DMD: EMBARK 2-year results. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-18, 2025; Dallas, TX. Abstract P169.
- www.sarepta.com/community-letter-elevidys-safety-update
Co-author:
Nicolas Dubuisson, 1. Neuromuscular Reference Centre UCL Saint-Luc, University of Louvain, Brussels, Belgium; 2. Oxford Neuromuscular Centre, Department of Neurology, John Radcliffe Hospital, Oxford, UK
Publish on behalf of the Scientific Panel on Muscle and NMJ disorders