5-Year Outcomes Add Supportive Evidence to Approved Gene Therapy for Duchenne

Jerry R. Mendell, MD

In an update to the phase 1 Study 101 (NCT03375164), results showed that treatment with delandistrogene moxeparvovec (Elevidys; Sarepta), an FDA-approved gene therapy for patients with Duchenne muscular dystrophy (DMD) was safe over a 5-year treatment period, with outcomes that support the therapy’s role in stabilizing or slowing DMD disease progression.¹

Study 101 featured 4 patients with DMD, aged between 4 and 8 years old, received a single intravenous infusion of delandistrogene moxeparvovec, also known as SRP-9001, for a 5-year follow-up period. Overall, 75 adverse events (AEs) were reported throughout that time, most of which occurred within 70 days of post-infusion. There were 18 treatment-related treatment-emergent AEs reported, all of which were mild or moderate in severity, and the most common being vomiting and increased liver enzymes. Overall, the 5-year analysis found no serious AEs, clinically significant complement-mediated AEs, study discontinuations, or deaths.

In this post-hoc analysis, the 5-year data of those treated with the gene therapy were compared with a propensity score-weighted external control (EC) cohort (n = 17) at 4.5 years, which included patients from the FOR-DMD study (NCT01603407). The EC cohort's 5-year follow-up data was adjusted to a 4.5-year follow-up to align with Study 101's inclusion criteria, which required at least 12 weeks of a stable corticosteroid dose before baseline.

Led by Jerry R. Mendell, MD, an advisor to the Jerry R. Mendell Center for Gene Therapy, investigators observed a statistically significant and meaningful difference in time to rise (TTR) from the floor at year 5 among those treated with the gene therapy vs the EC cohort. Furthermore, 10-meter walk/run time was maintained amongst delandistrogene moxeparvovec-treated patients over 5 years, demonstrating a clinically meaningful difference vs the EC cohort at year 5.

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Compared with the EC cohort, those treated with the gene therapy showed a sustained increase in North Star Ambulatory Assessment (NSAA) total score over 5 years, with statistically significant and meaningful differences observed. Notably, all patients on the gene therapy remained ambulant throughout the study duration whilst 4 patients in the EC cohort experienced loss of ambulation at 8.4-11.6 years old. Furthermore, a previously developed cTAP model showed an increase in divergence of NSAA total score trajectory of delandistrogene moxeparvovec-treated patients vs their natural history predictions over 5 years of follow-up.

Delandistrogene moxeparvovec, an adeno-associated vector-based gene therapy, was originally approved under the accelerated approval pathway in June 2023, with data from Study 101 and 2 other lower-level studies supporting the decision. Earlier this year, the therapy gained traditional approval, as well as had its label expanded to include patients aged 4 years and older with DMD. At the time, the therapy also gained an accelerated approval for nonambulatory patients with the disease.²

The decision to expand delandistrogene moxeparvovec’s indication came shortly after Sarepta announced that the therapy failed to meet its primary end point in the phase 3 EMBARK study (NCT05096221). Over a 52-week treatment period, those treated with the agent saw a nominal difference in change on NSAA total score relative to placebo (SRP-9001 change: 2.6; n = 63; placebo: 1.9; n = 61). At week 52, key secondary end points, which included TTR, 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).³

REFERENCES
1. Mendell JR, Sahenk Z, Lowes LP, et al. Five-year outcomes with delandistrogene moxeparvovec in patients with Duchenne muscular dystrophy: a Phase 1/2a study. Presented at World Muscle Society; October 8-12, 2024; ABSTRACT 425P.
2. Sarepta Therapeutics Announces Expanded US FDA Approval of ELEVIDYS to Duchenne Muscular Dystrophy Patients Ages 4 and Above. News Release. Sarepta Therapeutics. Published June 20, 2024. Accessed October 8, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-expanded-us-fda-approval-elevidys?_ga=2.261745871.332981042.1718920455-330115727.1718920455
3. 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