(Bloomberg) -- Sarepta Therapeutics Inc.’s experimental gene therapy for a debilitating muscle disease that mainly affects boys doesn’t clearly show benefit and raises safety concerns, Food and Drug Administration staff said in documents posted ahead of a review by advisers from outside the agency.
Studies have failed to show unambiguous evidence that Sarepta’s candidate treatment for Duchenne muscular dystrophy will likely benefit patients, FDA staff said in a document published Wednesday ahead of the FDA advisory panel meeting scheduled for Friday. The FDA reviewers also voiced concern about potential safety issues with giving people a gene therapy if it turns out to be ineffective. If approved, Sarepta’s SRP-9001 would become the first gene therapy to treat muscular dystrophy.
“The documents create a shaky backdrop for the panel on Friday and call into question some of SRPT’s past statements about the existence of a highly statistically significant association between microdystropin expression and functional benefit,” SVB Securities analyst Joseph Schwartz said Wednesday in a note to clients.
Shares of Sarepta rose 1% at 9:49 a.m. in New York.
Duchenne muscular dystrophy occurs when a genetic mutation causes people to produce insufficient amounts of a protein called dystrophin that supports muscle cells. The condition results in weakness that worsens over time, and most patients die by their early 20s.
Sarepta’s drug delivers a gene that encodes for a smaller version of dystrophin, and the company is seeking approval based on the therapy’s ability to produce the protein microdystrophin. In a 41-patient trial, the drug increased microdystrophin levels but didn’t clearly improve overall function compared to a placebo after nearly a year.
Efficacy Concerns
Advisers will vote on whether the benefits and risks support an accelerated approval of SRP-9001 based on microdystrophin expression. The agency isn’t required to follow the recommendations of its advisory panels, but it often does. Members are also being asked to discuss whether microdystrophin is likely to predict clinical benefit, findings within the clinical trials and the fact that Sarepta plans to finish its proposed confirmatory trial by the end of September, among other issues.
The FDA has been discouraging Sarepta from using microdystrophin as a measure of the drug’s efficacy since 2018, according to the briefing documents. That year, the agency recommended Sarepta “choose an endpoint that assesses clinically meaningful benefit, as manifested by how a patient feels, functions, or survives.” FDA reiterated its concerns in meetings with Sarepta every year until Sarepta submitted an application for the drug last fall based on that marker.
Mixed results from studies in rats “suggest that microdystrophin expression is not a reliable predictor of functional benefit,” the FDA reviewers said. While the levels of microdystrophin do rise in patients who get the gene therapy, the microdystrophin is a significantly shortened protein that is a designed to fit into the small viral shells that are used to deliver the therapy. Thus, it “does not contain the full functionality of wild-type dystrophin,” the agency said.
However, SVB’s Schwartz notes that patient groups who want the drug to be approved have “back channels to decision makers” and that senior FDA officials “might be able to overrule rank and file FDA personnel who are likely taking a narrower view of the application.”
Confirmatory Studies
The company is seeking accelerated approval through an FDA program that allows drugs for serious conditions to gain clearance after showing only that they affect disease-related markers, such as scan or lab tests, suggesting a likelihood of effectiveness. Sarepta already has three muscular dystrophy drugs cleared through the program, which requires manufacturers to complete studies proving that their product benefits patients.
But confirmatory trials for drugs that have received accelerated approval can take years, and have sometimes been delayed. That has too often resulted in expensive drugs with uncertain efficacy remaining on the market for years, critics say.
None of Sarepta’s DMD drugs — including Exondys 51, which received accelerated approval in 2016 amid controversy over its effectiveness — have yet been proven to work, the staff noted.
“Importantly, the clinical benefit of these products remains unknown, as none of the confirmatory clinical studies have been completed,” agency staff said in the document.
For SRP-9001, Sarepta is conducting a larger trial to confirm effectiveness. It’s fully enrolled and results are expected by the end of this year, the company has said.
(Updates with share price in fourth paragraph and new details throughout.)
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