FDA AdComm Leans Yes on Sarepta DMD Gene Therapy


Committee members were mostly split, ultimately voting 8–6 in favor of the benefit-risk profile of SRP-9001 supporting accelerated approval.

The FDA Cellular, Tissue, and Gene Therapies Advisory Committee (AdComm) has voted positively on accelerated approval for Sarepta Therapeutics’ investigational gene therapy delandistrogene moxeparvovec (SRP-9001) for the potential treatment of Duchenne muscular dystrophy (DMD) ahead of its May 29, 2023, Prescription Drug User Fee Act action date.1

The committee was split, with 8 members voting yes, 6 voting no, with 0 abstains, to the question: Do the overall considerations of benefit and risk, taking into account the existing uncertainties, support Accelerated Approval of SRP-9001—using as a surrogate endpoint, expression of Sarepta’s microdystrophin at Week 12 after administration of SRP-9001—for the treatment of ambulatory patients with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene?

“The threshold of substantial evidence has to be met whether or not the product is being approved under the standard pathway or accelerated pathway... I think the totality of evidence that we reviewed today simply doesn’t rise to the threshold [required],” G. Caleb Alexander, MD, MD, a professor of Epidemiology and Medicine at the Bloomberg School of Public Health of Johns Hopkins University, said after voting no.1

The committee discussed topics such as the use of microdystrophin as a surrogate end point for predicting clinical benefit in patients with DMD and results from part 1 of the phase 2 SRP-9001-102 study (NCT03769116) which only showed statistically significant benefit in subgroups of patients aged 4 to 5 years and not in those aged 6 to 7 years.

WATCH NOW: Jeffrey S. Chamberlain, PhD, on Reviewing Micro-Dystrophin as a Surrogate Endpoint in DMD

“Overall, these results are encouraging without a doubt, but given these small numbers and the difficulty in interpreting the value in the younger group, it's hard to be very confident about what we're going to see when we have the results from the more definitive 301 study,” Susan Ellenberg, PhD, a Professor Emerita of Biostatistics, Medical Ethics, and Health Policy at the Perelman School of Medicine of the University of Pennsylvania, and a temporary voting member of the committee, said.1

Sarepta representatives addressed the stratified age results and attributed them to the placebo group not being well matched to the treatment group in the 6- to 7-year-old subgroup in terms of North Star Ambulatory Assessment (NSAA) score as compared with the 4- to 5-year-old subgroup, an issue that is aimed at being addressed in the ongoing, phase 3 confirmatory EMBARK study (NCT05096221; Study 301). Within Study 102, clinical benefit was clear in both groups when compared with external controls.

“Do not let perfection be the enemy of the greater good,” a caregiver and patient advocate said during the proceedings.1

Regarding the EMBARK study, the committee was also concerned with how accelerated approval may affect its completion, considering that Sarepta has still not completed the confirmatory study for eteplirsen, approved under the accelerated approval pathway in 2016 for DMD. The company has 2 other DMD therapies still in confirmatory studies after accelerated approval as well. Sarepta tried to alleviate these concerns by sharing a status update on EMBARK, which is fully enrolled, with a data update from part 1 of the study expected in early 2024.

Representatives from the FDA, including Mike Singer, MD, PhD, a clinical reviewer in the Office of Clinical Evaluation of the Division of Clinical Evaluation and General Medicine and the Office of Therapeutic Products at the Center for Biologics, Evaluation, and Research of the FDA, brought up concerns including the lack of rigidity in the NSAA and processing differences between the SRP-9001 product A used in the first study and the product B used in the remaining studies, which Singer characterized as having less purity. He also compared Sarepta’s microdystrophin to wild-type microdystrophin and pointed out how differences between the 2 raise more uncertainty that can’t be addressed by currently available data on SRP-9001.

“I don’t have any real concerns about the risk of the therapy. I think it’s well tolerated. But I remain concerned about the actual benefit and whether that’s been adequately demonstrated without a study that’s going to be using the commercial product. That’s my primary concern, coming from the field of gene therapy... I think that the confirmatory study needs to be completed,” Nirali N. Shah MD, MHSc, head of the Hematologic Malignancies Section in the Pediatric Oncology Branch and the Lasker Clinical Research Scholar at the National Cancer Institute, said about her negative vote.1 “I think that these patients deserve the best and there is an incredible impact on patient hope and the ability to complete the confirmatory study. I would feel better knowing that benefit was able to be shown using the product that patients are ultimately going to be receiving.”

The AdComm meeting was a curveball for Sarepta, as the company had announced in February 2023 that the FDA would not require such a meeting before the agency changed its mind in March 2023.2 Part of the FDA’s turnaround may have been due to the degree of discussion on microdystrophin as a surrogate endpoint in late 2022 and early 2023. One piece of the discussion was the Pathway Development Consortium (PDC)’s paper published in Human Gene Therapy that reviewed and advocated for microdystrophin’s use and the suitability of the accelerated approval pathway.3

“In the rare disease space, going over 10 years now, the FDA has documented that they’re willing to permit and accept regulatory flexibility, adaptive trial designs, and the use of natural history data for a control, like we see today, given the rarity and severity of rare diseases and unmet needs,” Buddy Cassidy, a patient advocate and person with DMD, said after voting yes.1

Across Study 102, the phase 1/2 Study 101 (NCT03375164), and the phase 1 ENDEAVOR study (Study 103; NCT04626674), SRP-9001 has been well tolerated and yielded clinical improvements and biomarker expression after 1,2, and 4 years of treatment.4 The confirmatory EMBARK study’s primary endpoint is the change in NSAA total score from baseline to week 52 compared with placebo, though secondary end points include microdystrophin expression, time to rise from floor, patient-reported outcomes, skills gained, incidence of adverse events, and changes in scores on 100- and 10-meter walk/run, Timed Stair Ascend 4 Steps, and Stride Velocity 95th Centile tests.

“At the end of the day, giving people a chance – the risk of 1 chance vs no chance and no help on the horizon,” Lisa Lee, PhD, the associate vice president for research and innovation, director of scholarly integrity and research compliance, and a research professor of population health sciences at Virginia Tech, explained her positive vote.1 “I think we owe it to the patients to help intervene, and we can trust that patients and clinicians are going to be educated enough to make good decisions on what’s right for their child.”

1. 74th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. May 12, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-may-12-2023-meeting-announcement-05122023
2. Sarepta Therapeutics Announces Advisory Committee Meeting will be Held for SRP-9001. News release. Sarepta Therapeutics. March 16, 2023. Accessed March 17, 2023. https://www.businesswire.com/news/home/20230316005693/en
3. Chamberlain J, Robb M, Braun S, et al. Micro-dystrophin expression as a surrogate endpoint for Duchenne muscular dystrophy clinical trials. Human Gene Therapy. Published online January 24, 2023. doi:10.1089/hum.2022.190
4. 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 17, 2023. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-investigational-gene-therapy-srp-9001
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