FDA Grants Priority Review to Efficacy Supplement for Sarepta Therapeutics’ SRP-9001 Indication Expansion

Louise Rodino-Klapac, PhD

Credit: Sarepta Therapeutics

According to a recent announcement, the FDA has accepted and filed Sarepta Therapeutics’ efficacy supplement to the biologics license application (BLA) for the approved gene therapy SRP-9001 (Elevidys) for the treatment of ambulatory patients with Duchenne muscular dystrophy (DMD). The agency has granted the efficacy supplement a priority review with a review goal date of June 21, 2024, and has also confirmed no plan to hold an advisory committee meeting to discuss the supplement.¹

The goals of the efficacy supplement include expanding the labeled indication for SRP-9001 as a treatment for patients with DMD who have a confirmed mutation in the DMD gene. In the statement, the company also noted the supplement will include converting the SRP-9001 accelerated approval—granted by the FDA last June—to a traditional approval.

"Appreciation for the FDA and their engagement throughout this process – they have moved quickly to provide us with guidance and in granting priority review. The target review date of June 21 speaks to their commitment to urgency in considering the evidence included in the supplement that supports treatment with SRP-9001," Louise Rodino-Klapac, PhD, chief scientific officer and executive vice president of R&D at Sarepta, told NeurologyLive®. "Happy and hopeful for patients and families – the totality of evidence that we have seen in our clinical program supports the conclusion that SRP-9001 is modifying the trajectory of Duchenne and today’s news brings us one step closer to having this treatment available to as many individuals with Duchenne as possible."

In October 2023, the company announced topline data from the phase 3 EMBARK study (NCT05096221), a trial aimed to reinforce the SRP-9001's efficacy for the treatment of ambulatory patients with DMD.² Data from the 2-part, crossover, placebo-controlled study showed that patients with DMD aged 4 to 7 years old improved 2.6 points on the North Star Ambulatory Assessment (NSAA) total score, the primary end point, 52 weeks after treatment started. In comparison, those on placebo improved 1.9 points, a difference of 0.65 points that was not statistically significant between groups (P = .24). In addition, treatment with the therapy resulted in robust changes on all key pre-specified functional secondary end points over the treatment period.

In EMBARK, eligible patients received a single dose of SRP-9001 during either Part 1 or Part 2 of the study. In Part 1, participants (n = 125) were randomized according to age (≥4 to <8 years) or NSAA total score at screening (>16 or <29) and received either 1.33 x 1014 vg/kg of SRP-9001 or placebo with a follow-up period for 52 weeks. Following Part 1, patients crossed over to the opposite treatment for Part 2 of the study, where they are being followed for 52 weeks. All patients remain blinded.

Across secondary end points, investigators recorded a least square mean (LSM) difference of –0.64 (P = .0025) in change on time to rise (TTR) for SRP-9001-treated patients vs placebo. The effects of the agent were more pronounced among 6- and 7-year-old treated patients (LSM change vs placebo, –0.78; P = .0291) than among patients aged 4-5 (LSM change vs placebo, –.50; P = .0177). Similarly, the agent resulted in clinically meaningful treatment effects on 10-meter walk test (LSM change vs placebo, –0.42; P = .0048), with higher impacts observed among those aged 6-7 years old (LSM change vs placebo, –0.52; P = .0363) than those aged 4-5 years old (LSM change vs placebo, ­–0.33; P = .0319).

"Duchenne is a relentlessly progressive disease and every day patients lose muscle function that they cannot get back. The goal of treatment with SRP-9001 is to stabilize and potentially halt the progression of Duchenne," Klapac said. "The clinical data support the conclusion that SRP-9001 modifies the trajectory of Duchenne, demonstrating a treatment benefit that is clinically meaningful and similar regardless of age; therefore, we believe all patients with Duchenne can benefit from treatment with SRP-9001. This is supported by what we are hearing and seeing from clinicians and patients. For example, clinicians have repeatedly referenced the quality of the movement they see in patients after treatment."

SRP-9001, otherwise known as delandistrogene moxeparvovec, was approved by the FDA in June 2023 as the first gene therapy for patients with DMD with a confirmed mutation in the DMD gene.³ An AAV vector-based gene therapy, SRP-9001 was approved based on data from several studies, including the phase 1/2 SRP-9001-101 (NCT03375164), the phase 2 SRP-9001-102 study, and the phase 1 ENDEAVOR study (SRP-9001-103; NCT04626674). The medication is indicated for ambulatory pediatric patients aged 4 to 5 years with DMD and is contraindicated for those with any deletion in exon 8 and/or exon 9 in the DMD gene.

Douglas S. Ingram

Credit: Sarepta Therapeutics

"Current treatments are limited to steroids or, in the case of Sarepta’s exon-skipping medicines, are only available to a subset of patients (just under 30% of patients are amenable to exon-skipping 51, 53 and 45) so there is still significant unmet need in Duchenne. SRP-9001 is the first treatment that addresses the root cause of the disease that could reach the majority of those with Duchenne," Klapac added.

The company is currently working under a signed collaboration agreement with Roche to shape the future of care for the Duchenne community, aiming to enable those living with neuromuscular disease to maintain and protect their muscle function.¹ Based on the released statement, Sarepta is responsible for regulatory approval and commercialization of SRP-9001in the United States as well as manufacturing and Roche is responsible for regulatory approvals and bringing SRP-9001 to patients across the rest of the world.

"We are pleased to announce that FDA has accepted and filed Sarepta’s Efficacy Supplement to evaluate broadening the approved indication of SRP-9001 by removing age and ambulation restrictions and converting the approval from accelerated to traditional,” Douglas S. Ingram, the president and chief executive officer at Sarepta, said in a statement.¹ “We are particularly grateful for the Division’s prompt engagement and commitment to expediency by granting priority review and setting a June 21 review goal date. Understanding that every day matters to families living with Duchenne, we will work with our regulatory counterparts to successfully complete this review as rapidly as possible."

REFERENCES
1. Sarepta Therapeutics Announces U.S. FDA Acceptance of an Efficacy Supplement to Expand the ELEVIDYS Indication. News Release. Sarepta Therapeutics. Published February 16, 2024. Accessed February 16, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-us-fda-acceptance-efficacy
2. Sarepta Therapeutics announces topline results from EMBARK, a global pivotal study of ELEVIDYS gene therapy for Duchenne muscular dystrophy. News release. Sarepta Therapeutics. October 30, 2023. Accessed February 16, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-topline-results-embark-global-0
3. Sarepta Therapeutics announces FDA approval of Elevidys, the first gene therapy to treat Duchenne muscular dystrophy. News release. June 22, 2023. Accessed February 16, 2024. https://www.businesswire.com/news/home/20230622454844/en/