Elevidys halted in nonambulatory DMD after second death reported
Gene therapy's developer Sarepta will overhaul drug's safety plans
A second person with Duchenne muscular dystrophy (DMD) has died of acute liver failure after being treated with the one-time gene therapy Elevidys (delandistrogene moxeparvovec-rokl).
A first death was announced in March and both occurred in people with DMD who were no longer able to walk. Following the deaths, the gene therapy’s developer Sarepta is overhauling its safety plans for Elevidys.
“We are deeply saddened by the loss of a second patient and extend our heartfelt condolences to the patient’s family and his care team during this incredibly difficult time,” Louise Rodino-Klapac, PhD, Sarepta’s chief scientific officer and head of research and development, said in a company press release. “Our paramount priority is the safety and well-being of the patients we serve. We are taking immediate, decisive steps to better understand and mitigate the risk of acute liver failure … for those with Duchenne who are nonambulatory.”
In a letter to the DMD community, the company announced it will suspend commercial shipments of Elevidys for DMD patients who cannot walk. In the U.S., Elevidys is fully approved for DMD patients, ages 4 and older, who can walk and it’s conditionally approved for patients, ages 4 and older, who cannot walk.
“We know that an update like this is difficult for families. We promise to continue sharing as we learn more,” the company stated.
Meanwhile, Roche, which holds the rights to market Elevidys outside the U.S., will discontinue Elevidys for nonambulatory patients in the commercial setting. The new restrictions from Sarepta and Roche don’t affect Elevidys for patients who can walk.
Halting clinical studies
“Patient safety is always our highest priority. Therefore, we have recommended halting treatment with Elevidys in nonambulatory patients with immediate effect,” Levi Garraway, MD, PhD, Roche’s chief medical officer and head of global product development, said in a company press release.
In its own letter to the community, Roche said it will continue to provide relevant updates as new information becomes available.
In addition to halting shipments of Elevidys for nonambulatory patients, Sarepta and Roche are pausing several clinical trials including ENVISION (NCT05881408), a Phase 3 study Sarepta is sponsoring to test the gene therapy in ambulatory and nonambulatory DMD patients. ENVISION had finished screening and dosing in the U.S., but sites in other countries had still been screening and dosing.
In Europe, two other trials, ENVOL (NCT06128564), sponsored by Roche to test Elevidys in children younger than 4, and a Phase 1 study (NCT06241950) testing the therapy in patients with preexisting antibodies against the viral vector used in the gene therapy, are also being paused.
Sarepta said it will work to create a new safety protocol to minimize patient risk and hopes to resume dosing in ENVISION following alignment on the protocol with the U.S. Food & Drug Administration (FDA).
DMD is caused by mutations in the gene that provides instructions to make dystrophin, a protein vital for muscle health. Elevidys delivers a gene encoding a shortened, but functional version of dystrophin, to muscle cells. The therapy delivers its payload using a viral vector, essentially a virus engineered to deliver a therapeutic gene instead of causing an infection.
Viral vectors are useful for gene therapy, but the immune system cannot tell the difference between them and an infectious virus. As such, gene therapies using viral vectors can trigger an inflammatory response, particularly in the liver when the therapy is infused into the bloodstream. As detailed in its current prescribing information, acute liver injury is a known possible side effect of Elevidys and high levels of liver damage markers typically are seen within the first eight weeks of treatment.
Sarepta hopes to develop an updated protocol that will use enhanced immune-suppressing regimens to minimize the risk of problematic reactions. The company said it will convene a panel of experts to evaluate data and assess a proposed regimen that Sarepta says is supported by preclinical data. The company will share the panel’s recommendations with the FDA to obtain regulatory guidance and allowance.
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