Liver Failure-Associated Death Reported in Patient Treated With Sarepta Gene Therapy Elevidys

A patient has died following treatment with Elevidys, the Sarepta Therapeutics product that is the only FDA-approved gene therapy for Duchenne muscular dystrophy, the company disclosed Tuesday.

The patient, a young man, suffered acute liver failure after receiving the therapy, Sarepta said. Liver injury is a known complication risk of Elevidys and other gene therapies that use an adeno-associated (AAV) virus to deliver these one-time treatments to cells. That risk is already flagged on the Elevidys label. But acute liver injury leading to death has not been previously reported in clinical testing or real-world use of Elevidys.

Cambridge, Massachusetts-based Sarepta said testing revealed the patient who died had a recent cytomegalovirus (CMV) infection that the treating physician identified as a potential contributing factor to the death. This infection can damage the liver, leading to CMV hepatitis, which can become fatal in those with weakened immune systems.

In Duchenne, genetic mutations lead to deficiency of a key muscle protein called dystrophin. This rare disease, which affects mostly boys, leads to progressively worsening muscle function that typically robs patients of the ability to walk by the age of 12. Declining lung and heart function can lead to death in a patient’s 20s or early 30s.

Elevidys gets a patient’s muscle cells to produce a smaller version of dystophin. The gene therapy won accelerated FDA approval in 2023 for patients ages 4 and 5, but went on to fail its confirmatory Phase 3 test. Last June, Elevidys converted its status to full FDA approval for Duchenne patients age 4 and older who can still walk. For non-ambulatory patients, the therapy’s status is an accelerated approval that requires another confirmatory study. The decision was a controversial one that came only after a top FDA official overruled agency staff regarding the gene therapy’s efficacy.

In January, Sarepta reported new Phase 3 results showing that participants in the second part of the two-part study showed improvement measured at one year, according to a rating assessment for Duchenne patients. No new safety signals were reported at that time.

Shares of Sarepta sank about 20% following the fatality announcement Tuesday, but analysts who follow the company described the investor reaction as overblown. William Blair analyst Sami Corwin said in a research note that this is the first Elevidys-related death. Fatalities have also been reported following the launch of Novartis’s Zolgensma, an AAV-delivered gene therapy for spinal muscular atrophy. She added that the recent CMV infection could have exacerbated the Duchenne patient’s condition, suggesting additional safety screening measures could be used to prevent future deaths.

The patient’s age may have been a contributing factor, Leerink Partners’ Joseph Schwartz said in a research note. Older Duchenne patients have higher morbidity. Also, Elevidys is dosed according to patient weight. An older, heavier patient would require a higher dose. Sarepta management told Leerink it believes this case is “very unique,” reiterating this is the first fatality in more than 800 patients who received Elevidys in clinical trials or as a prescribed therapy.

“Although we acknowledge that such severe side effects associated with mortality can certainly be alarming and cause the community to question the risk/benefit of treating older patients, we believe that the very low overall incidence which we estimate at less than 0.125% based on aggregate exposure to date is encouraging,” Schwartz wrote. “While fewer non-ambulatory patients have been treated with Elevidys so far (>100 since June 2024), the rate is still less than 1% which can still be considered low.”

Schwartz said that while Elevidys continues to have a favorable risk/benefit profile, the fatality could provide a lift for companies developing next-generation gene therapies for Duchenne. Regenxbio and Solid Biosciences use different capsids and transgenes in their respective gene therapies.

The higher risk for non-ambulatory Duchene patients appears to have precedent. In 2021, a patient treated with an experimental Pfizer gene therapy for Duchenne died in a clinical trial, leading to a clinical hold. The study enrolled ambulatory and non-ambulatory patients; Pfizer said the patient death was in the non-ambulatory cohort. Though Pfizer was later cleared to resume testing, the gene therapy failed in Phase 3. Last summer, Pfizer discontinued this program.

Sarepta said it has reported the fatality to health authorities and the company intends to update the prescribing information to represent the event. The company has also informed clinical trial investigators and prescribing physicians.

Photo by Sarepta Therapeutics