Duchenne Gene Therapy Delandistrogene Moxeparvovec Shows Manageable Safety Over 5-Year Period

Jerry Mendell, MD

(Credit: Nationwide Children's Hospital)

Delandistrogene moxeparvovec (Elevidys; Sarepta), a FDA-approved rAAVrh74 vector-based gene therapy that delivers a microdystrophin transgene to slow Duchenne muscular dystrophy (DMD) progression, demonstrated consistent safety outcomes across a broad population of patients with the disease, according to pooled clinical trial data recently presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas.¹

The pooled analysis included 156 patients from 4 clinical trials—Study 101 (NCT03375164), Study 102 (NCT03769116), ENDEAVOR Cohorts 1-5b (NCT04626674), and EMBARK Part 1 (NCT05096221)—with up to 5 years of follow-up as of January 15, 2024. Patients ranged in age from 3.2 to 20.2 years (mean, 6.7 years) and had a mean weight of 24.6 kg (range, 12.5-80.1 kg). Of the total patients, 95% (n = 148) were ambulatory at baseline.

Treatment-related, treatment-emergent adverse events (TR-TEAEs) occurred most frequently within 90 days of therapy administration. Presented by Jerry Mendell, MD, advisor to the Jerry R. Mendell Center for Gene Therapy, the most common TR-TEAEs reported in at least 15% of patients included vomiting, nausea, decreased appetite, increased glutamate dehydrogenase levels, and upper abdominal pain. Notably, most of these events resolved spontaneously or with appropriate management.

Serious treatment-related adverse events (AEs) were primarily liver-related, with 8 events involving liver abnormalities. Other serious AEs included rhabdomyolysis (events, n = 4), vomiting (events, n = 3), myocarditis (events, n = 2), immune-mediated myositis (events, n = 2), nausea (events, n = 1), and pyrexia (events, n = 1).

Safety outcomes were consistent across age and disease progression subgroups, including ambulatory patients aged 3 years to 7 years (n = 141), ambulatory patients aged 8 years to 13 years (n = 7), and nonambulatory patients aged 9 years to 21 years (n = 8). Importantly, there were no clinically significant AEs related to complement activation.

As of January 15, 2024, no deaths or study discontinuations had been reported. The overall safety and tolerability profile of delandistrogene moxeparvovec was considered manageable, regardless of age, weight, or disease stage. Overall, these findings supported the continued investigation and use of delandistrogene moxeparvovec as a gene therapy option for patients with DMD.

READ MORE: MDA Study Highlights Lack of Psychosocial Care Services for Duchenne Muscular Dystrophy

Delandistrogene moxeparvovec, a gene replacement therapy initially granted accelerated approval in June 2023, recently expanded its label to include both ambulatory and nonambulatory patients over 4 years of age. The approval was based on data from 3 clinical trials of SRP-9001 which included the phase 1/2 SRP-9001-101 (NCT03375164) study, the phase 2 SRP-9001-102 study, and the phase 1 ENDEAVOR study (SRP-9001-103; NCT04626674). Overall, the treatment was approved based on changes in a surrogate end point—the expression of microdystrophin—from several of these different trials.

Although clinical trials reported predictable and manageable safety outcomes, real-world data presented at the 2025 MDA Conference has provided additional insights into the therapy’s tolerability and highlighted rare but serious AEs.² In a retrospective chart review conducted at the Neuromuscular Clinic at Children’s Health Dallas, 14 patients with confirmed DMD were treated with delandistrogene moxeparvovec between July 2023 and December 2024. The mean age at the time of treatment was 6.5 years, with the oldest patient being 14 years old and nonambulatory. Patients varied in their pretreatment steroid regimens: 6 were steroid-naïve, 6 were on daily steroids, and 2 were on a weekend regimen. All transitioned to high-dose daily steroids post treatment, as recommended by the therapy's label.

Presented by lead author Lauren Hendrix, BSN, RN, CPN, a nurse at Children's Health, mild gastrointestinal AEs were the most commonly reported AEs, which was consistent with the previous clinical trial data. Among the 14 patients, 11 experienced nausea, vomiting, or decreased appetite and mild myalgia was noted in 1 patient.

Serious AEs were rare but significant. One patient experienced acute liver injury, and another developed acute myocarditis—both required hospitalization and were treated with high-dose intravenous steroids. Additionally, 2 patients classified as high-risk because of the presence of late gadolinium enhancement on cardiac MRI underwent more frequent post treatment monitoring.

The findings reinforce the manageable safety profile of delandistrogene moxeparvovec observed in clinical trials, with gastrointestinal AEs remaining the most common. However, the occurrence of serious events like myocarditis and liver injury underscored the need for continued vigilance and monitoring. Further real-world data may be essential to fully understand the prevalence and management of these potential risks in a broader DMD population.

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REFERENCES
1. Mendell J. Long-Term Safety and Tolerability of Delandistrogene Moxeparvovec in Duchenne Muscular Dystrophy: Phase 1 to Phase 3 Clinical Trials. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract P89.
2. Hendrix L, Castillo ZG, Batley K. Adverse Events post gene therapy in patients with Duchenne Muscular Dystrophy: A single center experience. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract P70.