Delandistrogene moxeparvovec (Elevidys; Sarepta), a gene therapy for Duchenne muscular dystrophy (DMD), continues to show promise in long-term studies. Recent data from a 5-year follow-up of the phase 1 Study 101 and cardiac safety data from the phase 3 EMBARK trial provide further insights into the therapy's efficacy and safety profile. These findings were presented at the World Muscle Society 2024 and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting.
Long-Term Efficacy of Delandistrogene Moxeparvovec
The phase 1 Study 101 (NCT03375164) assessed the safety and efficacy of a single intravenous infusion of delandistrogene moxeparvovec in four patients with DMD aged 4 to 8 years over a 5-year period. The results indicated that the treatment was safe, with most adverse events occurring within 70 days post-infusion and being mild to moderate in severity. Notably, the 5-year analysis reported no serious adverse events, clinically significant complement-mediated adverse events, study discontinuations, or deaths.
A post-hoc analysis compared the 5-year data of these patients with a propensity score-weighted external control (EC) cohort (n = 17) from the FOR-DMD study (NCT01603407). Led by Jerry R. Mendell, MD, investigators observed a statistically significant difference in time to rise (TTR) from the floor at year 5 among those treated with the gene therapy versus the EC cohort. Furthermore, patients treated with delandistrogene moxeparvovec maintained their 10-meter walk/run time over 5 years, demonstrating a clinically meaningful difference compared to the EC cohort at year 5.
Compared to the EC cohort, the gene therapy group showed a sustained increase in the North Star Ambulatory Assessment (NSAA) total score over 5 years, with statistically significant differences observed. All patients on the gene therapy remained ambulant throughout the study, while four patients in the EC cohort experienced loss of ambulation at 8.4-11.6 years old. A previously developed cTAP model showed an increased divergence of NSAA total score trajectory in delandistrogene moxeparvovec-treated patients compared to their natural history predictions over 5 years of follow-up.
Cardiac Safety Profile
New findings from Part 1 of the phase 3 EMBARK study (NCT05096221) revealed that delandistrogene moxeparvovec did not adversely affect cardiac measures relative to placebo over a 52-week treatment period. The study, led by Glenn A. Walter, PhD, 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).
Analyses of cMRI left ventricular parameters, including ejection fraction, end diastolic volume, end systolic volume and mass, revealed no relevant differences between the gene therapy and placebo groups. An analysis of the global circumferential strain of the left ventricle also showed no significant differences between the active (mean change, –0.37) and placebo (mean change, 0.21) groups at week 52. Furthermore, analyses of the segmental circumferential strain parameters across different regions of the left ventricle revealed no relevant differences between the two treatment groups.
EMBARK Trial Outcomes
The EMBARK trial, a 2-part, multinational, double-blind, placebo-controlled study, randomized 125 ambulatory boys with Duchenne, aged 4 to 7 years, to either a single intravenous administration of delandistrogene moxeparvovec or placebo. The primary outcome was the change from baseline in North Star Ambulatory Assessment (NSAA) scores at 1 year. While the trial did not meet its primary endpoint (delandistrogene moxeparvovec change: 2.6; placebo: 1.9), key secondary outcomes, such as time to rise (TTR) and the 10-meter walk/run (10MWR), favored delandistrogene moxeparvovec.
At week 52, between-group differences in TTR (-0.64 seconds, 95% CI -1.06 to -0.23) and 10MWR (-0.42 seconds (95% CI -0.71 to -0.13) were clinically relevant. A pre-specified global statistical test on a composite of six functional endpoints showed a difference between delandistrogene moxeparvovec and placebo (P = 0.0044), indicating a functional treatment effect.
Safety and Tolerability
In the EMBARK trial, 674 adverse events were recorded with delandistrogene moxeparvovec and 514 with placebo. Treatment-related, treatment-emergent adverse events occurred in 76.2% of participants in the delandistrogene moxeparvovec group, with most being mild to moderate and resolving. Seven boys (11.1%) who received delandistrogene moxeparvovec experienced treatment-related serious adverse events, including acute liver injury, myocarditis, nausea, vomiting, pyrexia, and rhabdomyolysis, all of which resolved. There were no deaths, discontinuations, or clinically significant complement-mediated adverse events.
These findings support the continued evaluation and use of delandistrogene moxeparvovec as a therapeutic option for DMD, with a manageable safety profile and evidence of long-term functional benefits.
