In approving Sarepta's DMD gene therapy, FDA's Peter Marks overruled reviewers' rejection

The FDA's review teams were moving against an approval of Sarepta's Duchenne muscular dystrophy gene therapy. But Peter Marks, M.D., Ph.D., who oversees the agency's review of gene therapies, disagreed with the staffers' interpretations, a memo shows.

Sarepta’s $3.2 million Duchenne muscular dystrophy (DMD) gene therapy, Elevidys, won a long-awaited accelerated approval Friday in a restricted patient group.

As director of the FDA's Center for Biologics Evaluation and Research (CBER), Marks agreed with the review teams determination on Elevidys' product quality and safety, but ultimately disagreed with “certain interpretations of the efficacy data,” coming to “a different conclusion” in the 4 through 5 years old group, he wrote in a memo.

Marks learned of the internal objections and intervened, Stat reported in April. Instead of a decision right away, Marks sought outside input through an advisory committee meeting, according to Stat. During the May meeting, experts voted 8 to 6 in support of an accelerated approval of Elevidys, also known as SRP-9001

Marks read reviews and recommendations on the drug from several FDA branches, including the Office of Therapeutic Products (OTP), the Office of Compliance and Biologics Quality (OCBQ) and others before coming to his decision, he wrote.

The director found that the data Sarepta’s provided in its application met the mark for “substantial evidence of effectiveness.” He cited an exploratory analysis, which showed an increase in average change from baseline on a functional skills scale called the North Star Ambulatory Assessment (NSAA) for Elevidys compared with placebo in the 4-5 age group.

While the sample size in that set of data was small, Marks said that the outcome on the NSAA scale correlates with Elevidys’ micro-dystrophin protein expression. That “compelling” evidence, combined with the high unmet need of the disease, led to Marks’ call that the therapy meets the standard for accelerated approval in the specific age group.

However, the data in the 6-7 years old group shows that its “at least theoretically plausible” that the product might be less effective, Marks wrote. Part of that could be due to a change in underlying disease that occurs past age 6, providing more reason for approval in the younger age group so that patients don’t “irreversibly miss a window of opportunity” for the clinical benefits of the treatment, he said.

“Here, given the unmet medical need, the serious nature of the underlying disease entity, and the progressive and irreversible nature of the disease with onset in early childhood, it is reasonable to accept less certainty about effectiveness than in other circumstances,” Marks wrote.

The data supporting the therapy’s effectiveness has been widely debated, with even advisers who voted in favor of approval during an advisory committee meeting expressing “concern about the strength of clinical evidence,” the director noted. Before that advisory meeting, the FDA made its hesitations known in its briefing documents, which noted that the studies “do not provide unambiguous evidence” that the treatment was “likely beneficial” for the patient population.

Marks has been vocal about his eagerness to green-light gene therapies and support of the accelerated approval pathway. On an April webinar hosted by the lobbying group the Alliance for a Stronger FDA, the director emphasized his mission to create “some logarithmic progression towards more and more gene therapies being approved.” At that time, 12 gene therapies have been cleared with five approvals in 2022, according to Marks.