In one of the first major tests of the new FDA leadership’s regulatory philosophy toward gene therapies for rare diseases, the agency is investigating two Duchenne muscular dystrophy patient deaths following treatment with Sarepta Therapeutics’ Elevidys.
Sarepta reported the deaths in March and on June 16. Both patients were teenage boys who passed away after developing acute liver failure within two months after treatment with Sarepta’s one-time therapy.
Both Duchenne patients were non-ambulatory, meaning their disease had progressed to a stage where they could no longer walk independently.
“FDA is investigating the risk of acute liver failure with serious outcomes, including those such as hospitalization and death, following Elevidys, and is evaluating the need for further regulatory action,” the agency said in a safety communication Tuesday.
Elevidys’ current U.S. label includes a warning about the risk of acute serious liver injury, but not ones for liver failure or death, the agency noted. After the first patient death, Sarepta said it intended to work to update Elevidys’ prescribing information accordingly.
In a statement to Reuters, the company said the FDA's communication “was triggered by our report to the FDA and our suggested update to the label to include information relating to the recent events.”
Liver toxicity is a known side effect among adeno-associated virus vector-based gene therapies like Elevidys. Following the deaths, it seems appropriate to at least elevate Elevidys’ liver safety alert to a black box warning, the highest level of safety-related warning on a medication’s label in the U.S.
There’s also the possibility that Elevidys may be banned among non-ambulatory patients, or be pulled entirely from the market.
In its Tuesday safety communication, the FDA’s language set the parameter for the investigation to focus on the drug’s use in non-ambulatory patients.
Following the second death case, Sarepta said it was prepared to propose to the FDA an enhanced risk mitigation measure using the immunosuppressant sirolimus to manage liver toxicity in non-ambulatory patients. Sarepta noted that the FDA had proactively asked if the company has considered using additional immunosuppression, including sirolimus, suggesting that a complete restriction in this population seems unlikely.
A full market withdrawal is not out of the question, though. Elevidys’ initial accelerated approval in a small age group—and a following nod in a broader population—stirred controversy after the then-director of the FDA’s Center for Biologics Evaluation and Research (CBER), Peter Marks, M.D., Ph.D., overruled negative opinions from the agency’s own review team.
Marks’ successor, Vinay Prasad, M.D., has been openly critical of the approvals of Elevidys.
Marks “[o]verturned 3 reviewers to approve a [Duchenne] gene therapy that seems to be killing children and blowing their livers up,” Prasad wrote on X in March following Marks’ surprise ouster from the FDA, apparently referring to Elevidys. Prasad became the new CBER head in May.
Adding to the uncertainty is the reported ousters of Nicole Verdun, who was tasked to lead the FDA “super office” overseeing cell and gene therapeutics under CBER, and her deputy Rachael Anatol, Ph.D.
Meanwhile, the outcome of the safety investigation into Elevidys could offer industry watchers one of the first concrete signs of the new FDA leadership’s tolerance of novel cell and gene technologies for rare diseases. Top U.S. health officials, including Prasad, hinted at regulatory support for the cell and gene therapy field at a recent roundtable meeting.
“Pediatric and rare diseases are completely neglected and things completely on our radar,” Prasad said at the meeting earlier this month, as quoted by Stat. “We are fully committed to being flexible.”