UPDATED: FDA advisers narrowly vote in favor of Sarepta's DMD gene therapy

FDA advisers have narrowly voted in favor of Sarepta Therapeutics' gene therapy for patients with Duchenne muscular dystrophy (DMD), a stunning decision that runs counter to regulators who expressed skepticism heading into the meeting. 

Experts from the Cellular, Tissue, and Gene Therapies Advisory Committee narrowly voted 8 to 6 that the benefit-risk profile of SRP-9001 was strong enough to support accelerated approval even as questions about the gene therapy's efficacy linger. No members of the committee abstained. SRP-9001 was developed to treat ambulatory patients with a DMD gene mutation.

Advisers were tasked with considering four discussion topics about SRP-9001 that centered on the available data on the treatment, the benefit-risk profile of administering it and the implications of allowing the company to use an ongoing phase 3 trial as a confirmatory study. There was little alignment between Sarepta and the FDA's interpretation of the data, forcing advisers to break the tie. 

"I think we owe it to the patients to help them intervene," said committee member and consumer representative Kathleen O’Sullivan-Fortin, who voted in favor. Others expressed confidence in the safety profile of the gene therapy even amid concerns about the efficacy. 

Sarepta argued that a surrogate endpoint quantifying the expression of micro-dystrophin protein in patients’ muscles was an adequate biomarker to predict clinical benefit and grant accelerated approval. The company cited a natural history study as evidence that correcting the expression addresses the root cause of DMD. The FDA has for years been wary of the proposed biomarker, suggesting as far back as 2018 that Sarepta reconsider the endpoint.  

Some of the concerns raised by both committee members and the FDA were aimed at Sarepta's manufacturing of SRP-9001, which changed between the second and third clinical trials. The new process, which uses a lower percentage of full capsid, is what Sarepta is using in its accelerated approval application. The agency cautioned this could reduce efficacy and increase the risk of side effects. It also wasn't the process used in Sarepta's most detailed clinical trial, part of Study 102. 

That trial was the only randomized, placebo-controlled study of the gene therapy conducted to date. The trial found that there was not a statistically significant change in functional motor ability between treated patients and placebo as assessed by a common functional rating scale for DMD. Sarepta argued that treated patients had a numerically greater score at all time points, but the FDA concluded those figures were within the bounds of uncertainty, “which is also demonstrated by the lack of even a trend toward statistical significance.”   

Sarepta pointed to a post hoc analysis to show that the results varied by age, however, with treated patients ages 4 to 5 showing improvement compared to placebo while 6- to 7-year-old patients had worse function scores than placebo. Sarepta used external control groups from natural history studies to prove a larger benefit between treated and untreated patients across the company’s studies to date. But the FDA said Friday that the natural history data are "challenging to interpret." 

The safety data ultimately proved incredibly valuable, namely that no patients died or discontinued the study therapy due to adverse events. Still, more than 1,200 side effects were reported among 85 evaluable patients, including 13 serious cases. FDA reviewers also raised concerns about potential cross-reactivity with other potential adeno-virus vector gene therapies, but a number of advisers were wary of giving that too much consideration given the swiftness with which patients with DMD deteriorate.

The advisers' ultimate decision runs counter to the FDA's briefing document that noted “the clinical studies conducted to date do not provide unambiguous evidence” that the treatment was “likely beneficial” for the patient population. Even Wall Street was wary of Sarepta’s chances, including analysts at Mizhuho who said in the days before the meeting that “it could be challenging for the AdCom to have a positive recommendation.” Researchers at Evercore believe there’s a 50% to 60% chance SRP-9001 is granted accelerated approval. The FDA’s decision date is May 29, and the agency does not have to follow the committee's recommendation. 

"Today’s advisory committee outcome is extremely important to the patient community, who are in urgent need of new therapies,” said President and CEO Doug Ingram in a statement. “With the May 29 action date our top priority, we will work collaboratively with the FDA to complete the review of our BLA for SRP 9001."

It's a welcome change of course for Sarepta after advisers voted against the company’s first DMD treatment in 2016, citing similar concerns about the lack of convincing data. Sarepta at the time was hoping to win accelerated approval based on data from just 12 patients. The FDA ultimately disagreed with its advisers, granting accelerated approval five months later. 

Patient advocates played a critical role in the vote Friday, pleading with officials that they deserved another treatment option. 

"There is nothing ambiguous about these improvements," said Brent Furbee, whose son Emerson was treated in Sarepta's 103 trial and has had an improvement in motor function and mobility.

Committee member Steven Pavlakis, M.D., said he trusted the testimonials from clinicians during the public hearing portion.

"I decided that there's some very good clinicians here that think it really does work," he said. "And that's how we do a lot of clinical science."

Sarepta may ultimately have Peter Marks, M.D., Ph.D., to thank for its newfound momentum. An investigation from Stat found that regulators were leaning toward rejecting the treatment outright before Marks, director of the FDA’s Center for Biologics Evaluation and Research, intervened. It was at his request that Friday’s advisory meeting was convened.

Marks said Friday that the agency decided to convene the advisory committee when it "became apparent that this would benefit from an open public discussion." He said that there wasn't "anything substantial that changed internally." 

Editor's note: This story has been updated with a statement from Sarepta CEO Doug Ingram.