Peter Marks, the head of the Food and Drug Administration office that oversees gene therapies, overruled other agency reviewers in clearing a new Duchenne muscular dystrophy treatment developed by biotechnology company Sarepta Therapeutics, a newly released document shows.
A memorandum written by Marks and made public Friday revealed he disagreed with the way other reviewers interpreted efficacy results supporting the treatment, now known as Elevidys, and felt it met the criteria for an “accelerated” approval in young children with Duchenne.
The FDA on Thursday approved Elevidys for Duchenne patients who are 4 through 5 years of age. That clearance was based on the treatment’s ability to produce a miniature form of the muscle-protecting protein Duchenne patients lack. The agency concluded production of that protein, called microdystrophin, is “reasonably likely” to lead to a health benefit for young kids.
Sarepta hasn’t proven that, however. In its only placebo-controlled trial, Elevidys didn’t produce a statistically significant improvement in motor function. The other data it brought to regulators were from studies that compared patients’ performance to historical data. Each showed promising signs that many patient advocates and researchers believe show that the treatment works.
But none of those findings are as conclusive as data from a placebo-controlled trial, the gold standard for clinical research. The FDA has conditioned its approval on Elevidys succeeding in such a study, an ongoing Phase 3 trial that’s expected to produce results by the end of the year. If that study succeeds, the agency could loosen the age restrictions for Elevidys. If it fails, the drug could be removed from market.
In documents filed ahead of the approval decision, FDA statisticians expressed skepticism about the evidence Sarepta compiled, arguing the company hadn’t provided “unambiguous evidence” Elevidys helps patients.
“It is challenging to conclude with reasonable certainty from the data provided by the applicant either that [the therapy] is likely effective for younger patients, or that it is likely ineffective for older patients or those with somewhat poorer functional status,” FDA staff wrote.
Still, an FDA panel voted narrowly in favor of an accelerated approval. A key reason why was an after-the-fact study analysis showing that, in the one placebo-controlled study Sarepta completed, children between 4 and 5 appeared to benefit the most.
Marks was convinced by that result as well. The evidence showed that 4- and 5-year-olds who were treated with Elevidys has an average 4.3-point increase from the study’s start on a commonly used test measuring their function, versus a 1.9-point increase in the placebo group. That outcome correlated with an increase in levels of the protein produced by the therapy, Marks wrote.
Even though Sarepta didn’t make such an evaluation a pre-specified study goal, Marks wrote the evidence is “compelling” and proves an association between protein expression and better health outcomes.
“Although I agree with the review team’s conclusions regarding product quality and safety, I disagree with certain interpretations of the efficacy data and come to a different conclusion regarding individuals ages 4 through 5 years,” Marks added.
“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,” he wrote.
Marks did agree with other reviewers that the historical comparisons Sarepta compiled were “challenging to interpret” and that the findings in 6- to 7-year-olds weren’t compelling. “In older children, it is at least theoretically plausible that the product may be less effective,” he wrote. Some experts have suggested that might be the case, given that patients’ muscles weaken with time and scar tissue builds up, making it more difficult for the therapy to have an impact.
Marks has publicly advocated for flexibility in reviewing gene therapies for rare inherited diseases. And in March, he reportedly pushed the agency to schedule the May advisory meeting after learning FDA scientists were leaning toward rejecting the treatment, according to Stat News.
Sarepta has been in this position before. Seven years ago, Janet Woodcock, then the FDA’s top drug evaluator, overruled her own review team in recommending an accelerated approval for a Duchenne medicine now known as Exondys 51. Woodcock concluded the drug’s effect on dystrophin levels were “reasonably likely” to result in a benefit.
The approval helped turn Sarepta into one of the biotech sector’s most valuable companies, and enabled it to invest in gene therapy research. It also caused a rift within the agency, with multiple reviewers leaving afterwards and criticizing Woodock’s decision.
Sarepta hasn’t yet proven, in a confirmatory trial, whether Exondys 51 can change the disease’s course. It has also used the accelerated approval pathway to bring two other, similar treatments — Amondys 45 and Vyondys 53 — to market.