SRP-9001 Improves Duchenne Muscular Dystrophy Disease Trajectory Despite Failing to Meet Primary End Point in Phase 3 EMBARK Trial

Jerry Mendell, MD

New findings from part 1 of the phase 3 EMBARK study (NCT05096221) assessing Sarepta Therapeutics’ gene therapy delandistrogene moxeparvovec (SRP-9001) showed that the agent failed to meet its primary end point in change among patients with Duchenne muscular dystrophy (DMD); however, did demonstrate several benefits on other secondary analyses.¹

Presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, treatment with the agent resulted in a nominal difference in change on North Star Ambulatory Assessment (NSAA) total score vs placebo over 52 weeks (SRP-9001 change: 2.6; n = 63; placebo: 1.9; n = 61). Using a cohort of ambulatory patients aged between 4 and 8 years with a confirmed DMD mutation within exons 18-79, there were no identified new safety signals, reinforcing the favorable safety profile observed to date.

Led by Jerry Mendell, MD, director of the Center for Gene Therapy at Nationwide Children’s Hospital, the trial comprised of individuals who had NSAA scores between 16 and 29 at screening, had recombinant adeno-associated virus serotype rh74 (AAVrh74) antibody titer less than 1:400, and were on a stable daily dose of oral corticosteroids for at least 12 weeks prior to the trial beginning. The study includes 2 parts, both of which are 52 weeks in length. In part 1, patients were randomly assigned 1:1 to either SRP-9001 or placebo, according to age at randomization and baseline NSAA. For the SRP-9001 group, a single, intravenous 1.33x1014 vg/kg linear standard dose was used.

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.

In June 2023, the FDA approved SRP-9001 as the first gene therapy for patients with DMD, indicated for those with ambulatory pediatric patients aged 4 to 5 years with DMD and contraindicated for those with any deletion in exon 8 and/or exon 9 in the DMD gene. Approved under the accelerated approval pathway, the phase 3 EMBARK study was designed to serve as a confirmatory study for agent.²

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SRP-9001 was approved based on changes in a surrogate end point—expression of microdystrophin—from several different trials. These 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).

In the 20-patient cohort 1 of ENDEAVOR, announced in July 2022, findings showed that SRP-9001-treated patients improved 4 points from their pre-therapy baselines on the NSAA compared with a propensity-weighted external control group (P <.0001) over a 1-year period. These patients demonstrated a 3.8-point (unadjusted means) and 3.2-point (least squared means) improvement that diverged from the natural history of DMD over time.³

In recent years, the treatment landscape for DMD has grown exponentially. In 2016, the FDA approved eteplirsen (Exondys 51; Sarepta), a treatment for patients amenable to exon 51 skipping, as the first approved therapy for the disease. Since then, there have been 4 other approvals, including 2 agents—viltolarsen (Viltepso; NS Pharma) and golodirsen (Vyondys; Sarepta)—that are indicated for patients with a confirmed mutation amenable to exon 53 skipping. Deflazacort (Emflaza; PTC Therapeutics), a derivative of prednisone, was approved for DMD in patients 2 years of age and older in 2017 as well. The most recent approval came in 2021, with the FDA greenlighting Sarepta’s casimersen (Amondys 45), an antisense oligonucleotide, for patients amenable to skipping exon 45.

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REFERENCES
1. 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
2. Sarepta Therapeutics announces FDA approval of Elevidys, the first gene therapy to treat Duchenne muscular dystrophy. News release. June 22, 2023. Accessed March 3, 2024.https://www.businesswire.com/news/home/20230622454844/en/
3. Sarepta Therapeutics’ investigational gene therapy SRP-9001 for Duchenne muscular dystrophy demonstrates significant functional improvements across multiple studies. News release. Sarepta Therapeutics, Inc. July 6, 2022. Accessed March 3, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-investigational-gene-therapy-srp-9001