DMD Gene Therapy Elevidys Shows Functional Benefit at 2 Years in Phase 3 EMBARK Trial

Two-year data from the phase 3 EMBARK clinical trial (NCT05096221) suggest that treatment with delandistrogene moxeparvovec (marketed as Elevidys) was associated with stabilization or slowing of functional decline in ambulatory children with Duchenne muscular dystrophy (DMD), compared with a matched external control cohort receiving standard-of-care corticosteroids.¹ Improvements in motor function measures including the North Star Ambulatory Assessment (NSAA), time to rise (TTR), and 10-meter walk/run (10MWR) were observed over 104 weeks, supporting the durability of the microdystrophin gene therapy approach.

DMD is a progressive X-linked disorder caused by pathogenic variants in the DMD gene leading to absence of functional dystrophin, resulting in muscle degeneration, loss of ambulation, and premature death from respiratory or cardiac complications.² Gene replacement strategies designed to deliver microdystrophin constructs have emerged as disease-modifying approaches.

EMBARK is a phase 3, randomized, placebo-controlled crossover study evaluating Elevidys in ambulatory boys aged 4 to younger than 8 years with DMD.¹ The therapy uses a recombinant adeno-associated virus serotype rh74 vector to deliver a microdystrophin gene to skeletal muscle.³

In part 1 of the study, 64 patients received a single infusion of delandistrogene moxeparvovec. Mean age at baseline was 5.98 years and mean NSAA score was 23.3 points.¹ Because patients assigned to placebo crossed over to active therapy after 1 year, longer-term comparisons were conducted against a propensity score–weighted external control cohort (n = 143) derived from the FOR-DMD trial and the PRO-DMD-01 and CINRG Duchenne Natural History Study cohorts.^1,4-6

At 2 years, treated patients demonstrated statistically significant differences versus external controls across several functional outcomes. Mean change in NSAA score from baseline was +2.63 points in the gene therapy group compared with −0.25 points in the external control cohort (least-squares mean difference, 2.88; 95% CI, 1.43-4.33; P = .0001).¹ Improvements were also observed in Time To Rise (difference −2.06 seconds; P = .0033) and 10-m Walk/Run (10MWR) (difference −1.36 seconds; P = .0028).¹

Velocity-based measures similarly favored treatment, including rise-from-floor velocity and 10MWR velocity. No treated patients lost the ability to perform functional assessments over the 2-year follow-up period. Muscle biopsy samples from a subset of participants demonstrated sustained microdystrophin expression, with mean levels of 34.29% of normal at week 12 and 45.68% at week 64.

The safety profile from weeks 52 to 104 was consistent with earlier analyses. Among 63 patients with 2-year follow-up data, 34 treatment-related adverse events occurred in 15 patients (23.8%). The most common events included elevations in troponin I and proteinuria.

One patient experienced 2 serious treatment-related events of rhabdomyolysis, both of which resolved with treatment. There were no treatment-related deaths or discontinuations in the study. Although, outside of the EMBARK trial, 2 treatment-related deaths from acute liver failure have been reported in older nonambulatory patients treated with Elevidys.

Elevidys received accelerated approval from the FDA in 2023 for ambulatory patients aged 4 through 5 years with confirmed DMD mutations.⁷ The indication was later expanded in 2024 to include ambulatory patients aged 4 years and older and selected nonambulatory patients.⁸ Approval was based primarily on microdystrophin expression and supportive functional data.

Interpretation of the EMBARK 2-year results is limited by reliance on an external control cohort rather than a randomized comparator beyond 1 year. External controls may have drawbacks such as greater variability across patients at baseline and disease management differences. In addition, the average corticosteroid dose in the external control cohort was not available, raising uncertainty about the extent to which steroid exposure may have influenced outcomes.

The authors concluded that Elevidys showed stabilization or slowing of disease progression at 2 years in comparison to the external control group. It was noted that the safety outcomes at 2 years were consistent with the trial’s safety outcomes at 1 year, and that no new safety signals appeared in the study’s second year.

REFERENCES
1. Two-Year Outcomes Following Delandistrogene Moxeparvovec Treatment in Ambulatory Patients With Duchenne Muscular Dystrophy: Phase 3 EMBARK Trial. Accessed February 23, 2026. https://clinicaltrials.gov/study/NCT05096221
2.Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy: part 1. Lancet Neurol. 2018;17(3):251-267.
https://doi.org/10.1016/S1474-4422(18)30024-3
https://doi.org/10.1212/WNL.0000000000002337
3. Mendell JR, Sahenk Z, Lehman K, et al. Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in Duchenne muscular dystrophy. JAMA Neurol. 2020;77(9):1122-1131.
https://jamanetwork.com/journals/jamaneurology/fullarticle/2766519
4. FOR-DMD Trial. ClinicalTrials.gov Identifier: NCT01603407.
https://clinicaltrials.gov/study/NCT01603407
5. Duchenne Natural History Study (CINRG DNHS). ClinicalTrials.gov Identifier: NCT00468832.
https://clinicaltrials.gov/study/NCT00468832
6. McDonald CM, Henricson EK, Abresch RT, et al. Long-term functional outcomes in Duchenne muscular dystrophy: CINRG DNHS. Lancet Neurol. 2013;12(8):760-768.
https://doi.org/10.1016/S1474-4422(13)70123-7
7. US Food and Drug Administration. ELEVIDYS (delandistrogene moxeparvovec-rokl) approval letter. 2023.
https://www.fda.gov/media/169679/download
8. US Food and Drug Administration. ELEVIDYS label update. 2024.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761348s002lbl.pdf