EMBARK Data Show Continued Improvements With DMD Gene Therapy

Encouraging long-term outcomes were seen in patients with Duchenne muscular dystrophy (DMD) who received the gene therapy delandistrogene moxeparvovec (Elevidys; Sarepta) in the EMBARK trial, according to findings presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference in Dallas, Texas, held March 16-19, 2025.

One-year data from the phase 3 EMBARK trial (NCT05096221) were published in November, showing that it did not achieve its primary end point of improving motor function.¹ Then, topline results from part 2 of EMBARK released by Sarepta this January, which included a crossover period, showed that participants receiving the gene therapy experienced clinically meaningful and statistically significant functional benefits compared with external controls.²

Results delivered today at the MDA meeting by Crystal Proud, MD, covered 2-year functional outcomes, gene expression, and safety from part 1 of EMBARK, which compared a treatment arm receiving delandistrogene moxeparvovec and a matched external control cohort of patients with DMD.³ In the 64 patients who received the intervention and 143 in the control cohort, mean ages were 5.98 and 6.24 years, respectively.

“At 2 years, the part 1 treated patients demonstrated statistically significant and clinically meaningful functional benefits compared with this propensity score–weighted external control cohort,” according to Proud, who is director of neurology and neuromuscular medicine at the Children's Hospital of the King's Daughters in Norfolk, Virginia.

The treated group showed a significant improvement in the primary end point of North Star Ambulatory Assessment score; theirs improved by 2.63 points while the control group worsened by 0.25 points, indicating a 2.88-point gap in favor of the intervention (P = .0001). They also showed faster time to rise, better rise from floor velocity, and superior 10-meter walk/run ability and velocity vs the control cohort.

Additionally, data showed that the intervention group’s micro-dystrophin expression levels were maintained to week 64, with localization to the sarcolemma. Safety outcomes were of particular interest to the audience given the news a day earlier that a young man with DMD had died after receiving delandistrogene moxeparvovec, having experienced acute liver failure.⁴ However, the data presented by Proud showed 2-year safety outcomes consistent with prior research. Most treatment-related, treatment-emergent adverse events were seen in the first 90 days; between weeks 52 and 104, 34 of these events occurred, but none led to death or discontinuation.³

Another poster delved into changes in muscle health assessed by MRI in patients who participated in EMBARK part 1, which were presented by Krista Vandenborne, PhD, professor at the University of Florida.⁵ An array of imaging measures used to quantify muscle makeup showed improved outcomes at week 52 in the delandistrogene moxeparvovec arm vs the placebo group, suggesting that the therapy stabilized or lessened the worsening of muscle function that occurs in the natural disease course.

“Quantitative MRI is a noninvasive methodology that is sensitive and can detect subclinical disease progression in Duchenne muscular dystrophy,” Vandenborne said. “The qualitative MR measures are objective. They are not dependent on patient growth, maturation, or motivation.”

Due to the small sample size—just 39 patients were included in this substudy—this analysis was not powered for statistical significance. Across 12 magnetic resonance parameters, a post hoc global statistical test yielded a P value of .0328. Following these data for another 52 weeks, the researchers observed some degree of progression of muscle pathology, although changes from baseline still favored the intervention over placebo in 3 of the 5 muscle groups examined.

References

1. Delandistrogene moxeparvovec fails to meet primary end point in phase 3 study. AJMC^®. November 15, 2024. Accessed March 19, 2025. https://www.ajmc.com/view/dmd-gene-therapy-elevidys-fails-to-meet-primary-endpoint-in-phase-3-study

2. McNulty R. EMBARK 2: delandistrogene moxeparvovec shows sustained benefits in DMD. AJMC. January 28, 2025. Accessed March 19, 2025. https://www.ajmc.com/view/embark-2-delandistrogene-moxeparvovec-shows-sustained-benefits-in-dmd

3. 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.

4. Sarepta Therapeutics shares safety update on Elevidys. News release. Sarepta; March 18, 2025. Accessed March 19, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-shares-safety-update-elevidys?_ga=2.125206282.1278883760.1742395347-1869754155.1740416635

5. Vandenborne K, Walter GA, Straub V, et al. Muscle MRI outcomes in patients with Duchenne muscular dystrophy treated with delandistrogene moxeparvovec: findings from EMBARK part 1. Abstract P168.