Duchenne Gene Therapy Shows No Alteration of Cardiac Outcomes in Phase 3 EMBARK Study

Author(s):

Key Takeaways

Delandistrogene moxeparvovec showed no adverse cardiac effects compared to placebo over 52 weeks in DMD patients.
The study involved 39 patients aged 4-8, with no relevant differences in cardiac measures between treatment groups.
Although the primary endpoint was unmet, secondary analyses showed benefits in functional assessments, supporting disease trajectory modification.
The EMBARK trial includes a crossover phase and open-label extension, continuing to evaluate long-term effects and safety.

After 52 weeks of treatment, no significant differences were found in cardiac MRI measures such as ejection fraction, end diastolic volume, or circumferential strain between the two groups.

Glenn A. Walter, PhD

New findings from Part 1 of the phase 3 EMBARK study (NCT05096221) revealed that delandistrogene moxeparvovec (Elevdys; Sarepta), an FDA-approved gene therapy for Duchenne muscular dystrophy (DMD), did not impact cardiac measures relative to placebo over a 52-week treatment period. After 1 year of treatment, investigators observed no adverse cardiac effects with the therapy, supporting its previously demonstrated manageable safety profile.

Presented at World Muscle Society 2024, a week 52 analysis of cMRI left ventricular parameters, including ejection fraction, end diastolic volume, end systolic volume and mass, revealed no relevant differences between those on the gene therapy vs placebo in the sub-study population. An analysis of the global circumferential strain of the left ventricle also revealed no relevant differences between the active (mean change, –0.37) and placebo (mean change, 0.21) groups at that time point.

Led by Glenn A. Walter, PhD, a professor and vice-chair of the department of physiology and aging at the University of Florida, the study included 39 patients with DMD, aged between 4 and 8 years old, who were randomly assigned to gene therapy (n = 19) or placebo (n = 20). The trial had an even split of patients who were between 4-5 (n = 19) and 6-7 (n = 20). After 52 weeks of treatment, analyses of the segmental circumferential strain parameters across different regions of the left ventricle revealed no relevant differences between the 2 treatment groups.

Coming into the study, the time since corticosteroid treatment started was 0.77 (SD, 0.53) and 0.91 (SD, 0.51) years for the delandistrogene moxeparvovec and placebo groups, respectively. At baseline, both groups had similar dosing weight, North Star Ambulatory Assessment (NSAA) scores, and time to rise (TTR) times. In the entire cohort, patients with a large deletion pathogenic variant represented nearly three-fourths (74.4%) of the sample, while small mutations accounted for the other one-fourth (25.6%).

EMBARK is a 2-part, multinational, double-blind, placebo-controlled trial in which patients with DMD were randomly assigned to either delandistrogene moxeparvovec or placebo for a 52-week period, followed by a crossover to the other treatment for another 52-week period. The study also includes an open-label extension after the crossover period, which lasts up to 5 years. The trial features only those with a confirmed DMD diagnosis, NSAA total scores between 16 and 29 at screening, and are on a stable daily dose of oral corticosteroids. In addition, patients must have rAAVrh74 total binding antibody titers less than 1:400.

The first portion of EMBARK was presented earlier this year at the 2024 Muscular Dystrophy Association Clinical and Scientific Conference. There, findings showed that the gene therapy failed to meet its primary end point in change on NSAA vs placebo (delandistrogene moxeparvovec change: 2.6; placebo: 1.9); however, did demonstrate several benefits on other secondary analyses. In addition, it continued to show a favorable safety profile, with no new identified safety signals.²

At week 52, key secondary end points, which included time to rise, micro-dystrophin expression, and 10-meter walk/run demonstrated treatment benefit in both age groups (4-5 and 6-7 years; P <.005). In addition, stride velocity 95th centile and time to ascend 4-steps showed benefit that was similar in magnitude and significant in the overall population (P <.005). "Based on the totality of functional assessments including the timed function tests, treatment with delandistrogene moxeparvovec indicates beneficial modification of disease trajectory," the study authors concluded.

REFERENCES
1. Walter G, Vandenborne K, Bourke J, et al. Cardiac MRI outcomes in patients with Duchenne Muscular Dystrophy treated with delandistrogene moxeparvovec: Findings from EMBARK Part 1. Presented at: World Muscle Society; October 8-12, 2024; ABSTRACT 428P
2. Mendell J, Muntoni F, McDonald C, et al. Safety and efficacy of delandistrogene moxeparvovec versus placebo in Duchenne muscular dystrophy (EMBARK): pivotal phase 3 primary results. Presented at: MDA Clinical and Scientific Conference; March 3-6; POSTER M164