A second patient has died following treatment with Sarepta Therapeutics’ Elevidys, raising more doubts about the Duchenne muscular dystrophy (DMD) gene therapy’s safety profile.
Sarepta and its ex-U.S. partner Roche reported the death early Sunday. Like the first case, disclosed in March, the patient died after developing acute liver failure (ALF) and was non-ambulatory, meaning the individual was no longer able to walk independently because of the progression of Duchenne.
As a result, Sarepta has suspended giving Elevidys to non-ambulatory patients in the commercial setting in the U.S. while the company seeks FDA approval of an enhanced risk mitigation measure involving the immunosuppressant sirolimus to manage liver toxicity.
For its part, Roche said it has simply “discontinued” Elevidys in commercial non-ambulatory patients outside the U.S.
Meanwhile, Sarepta has paused dosing in a clinical trial called Envision, which is serving as the confirmatory trial required by the FDA for Elevidys’ accelerated approval in non-ambulatory patients. The Massachusetts biotech aims to amend the trial protocol to add the prophylactic use of sirolimus, CEO Doug Ingram said on a conference call Monday.
As for Roche, European regulators had previously put three Elevidys trials, including Envision, on temporary clinical holds following the first death report.
The latest death was of a 15-year-old in the Envision study, Sarepta’s head of R&D, Louise Rodino-Klapac, Ph.D., said on the call. Without providing details, Rodino-Klapac said there were similarities and differences between the two incidents reported so far. In the first case, the deceased patient also had a recent cytomegalovirus infection, which can infect and damage the liver.
“We are currently evaluating this case in the context of this case alone, and then in comparison to the previous case,” Rodino-Klapac said. “We haven’t identified a single risk factor, but we are working expeditiously to identify anything that we could potentially point to in the absence of that.”
Liver damage is a classwide risk factor of existing gene therapies based on adeno-associated viral (AAV) vectors. The problem is believed to be related to a T-cell-mediated immune response to the AAV vector causing inflammation of the liver and, in rare cases, acute liver failure.
Acute serious liver injury is already listed in the “Warnings and Precautions” section of Elevidys’ label, and Sarepta has been looking to update it after the first death.
The two fatal liver failure cases happened after Elevidys was given to more than 900 patients globally, including 140 non-ambulatory patients.
While the dosing suspension in the U.S. and proposed risk mitigation method currently only affect non-ambulatory patients, three analysts on Monday’s call questioned whether similar measures should be applied to younger ambulatory patients, too, especially as liver toxicity has been seen in both populations.
“We are required to follow the evidence, and right now, the signal that we’ve seen is ALF in the non-ambulatory patient population,” Sarepta CEO Doug Ingram explained on the call.
But Ingram acknowledged that an enhanced regimen for ambulatory patients is a valid consideration and that “it’s certainly something that we will evaluate as we go on.” Once the proposed non-ambulatory protocol is in place, physicians will have the option to use sirolimus in ambulatory patients as well, he said.
About half of the DMD population is non-ambulatory, according to Ingram. Since Elevidys was initially approved in 2023 to treat ambulatory patients, about 30% of patients who got the one-time gene therapy this year were non-ambulatory, the CEO said.
During Monday’s call, Rodino-Klapac presented preclinical data in monkeys showing that sirolimus can lower T cells and suppress the immune response to Elevidys’ AAV vector. The immunosuppressant was also able to control elevations of liver enzymes in monkeys, while expression of the therapeutic gene included in Elevidys was not affected.
Sarepta has run the new risk mitigation measures by an expert panel and plans to meet with the FDA soon to discuss the plan, according to Ingram. Because the FDA has proactively asked if Sarepta has considered using additional immunosuppression, including sirolimus, Ingram said he believes the two parties will “have a very constructive discussion.”
As the two Sarepta execs noted, sirolimus has been used “pretty commonly” in other gene therapies, albeit in slightly different protocols.
The patient deaths mark another turn in Elevidys’ eventful journey. In 2023 and 2024, former director of the FDA’s Center for Biologics Evaluation and Research (CBER), Peter Marks, M.D., Ph.D., overruled the agency’s internal review team twice to grant Elevidys its original accelerated approval in a small patient group and then in a much broader population.
The second death has worsened Elevidys’ benefit-risk profile, and the liver toxicity concerns will likely linger and possibly even reach the ambulatory group, Jefferies analyst Andrew Tsai said in a Sunday note. Doctors were initially unfazed by the first patient death but hinted that they would not want to see the death rate increase, as families might then deny treatment rather than merely delaying infusions, Tsai noted.
The case also adds uncertainty to Elevidys’ future given that the newly appointed director of CBER, Vinay Prasad, Ph.D., had criticized its approval under Marks. On the bright side, Prasad, along with other U.S. health officials, pledged to facilitate the development of new cell and gene therapies during a roundtable discussion earlier this month.
Sarepta’s stock price tumbled nearly 50% on the news as of publication time Monday morning. The company has suspended its revenue guidance, hoping to provide an update in its second-quarter earnings report. The company had recently lowered its total 2025 revenue projection to between $2.3 billion and $2.6 billion from a previous range of up to $3.1 billion, solely because of its lower Elevidys sales outlook.