Sarepta's Elevidys Gets Boxed Warning for ALI and ALF

The FDA has updated the prescribing information for Sarepta Therapeutics' Duchenne muscular dystrophy (DMD) adeno-associated virus (AAV) vector-based gene therapy delandistrogene moxeparvovec-rokl (marketed as Elevidys).¹ Among the several changes are the addition of a boxed warning for risk of acute serious liver injury (ALI) and acute liver failure (ALF), removal of eligibility for nonambulatory patients, and expanded guidance for prescribers.

Specifically, the expanded guidance includes a modified oral corticosteroids regimen for before and after treatment, as well as recommendations for weekly enhanced monitoring in the 3 months after treatment. Sarepta also noted that it intends to evaluate an sirolimus immunosuppressive regimen aimed at reducing ALI and ALF risks with the hope of aligning with the FDA on a plan to allow for a return of eligibility of nonambulatory patients. In addition to the aforementioned changes to the prescribing information, the FDA also added a new Warnings & Precaution for heightened susceptibility to serious infections caused by immunosuppression.

“We want to thank the FDA for their thorough and collaborative review. Completion of the safety labeling change for Elevidys will ensure that families and healthcare professionals have clear information, supported by a Medication Guide, to help understand these updates and guide treatment decisions,” Louise Rodino-Klapac, PhD, the president of research & development and technical operations at Sarepta, said in a statement.¹

Earlier this year, Sarepta put a voluntary pause on shipments of Elevidys in the United States after 2 nonambulant patients who were treated with Elevidys died in separate incidents earlier this year.² Both of these patients’ deaths were attributed to acute liver failure (ALF).^3,4 The hold was initially only put on shipments for nonambulatory patients, but Sarepta later extended the hold to all shipments after the FDA made an informal request.⁵ Shortly after, the FDA recommended that the hold on ambulatory patients be lifted, but the hold for nonambulatory patients remained in effect.⁶

In addition to the deaths of patients treated with Elevidys, a 51-year-old patient treated with Sarepta’s investigational gene therapy SRP-9004 for nonambulant limb-girdle muscular dystrophy (LGMD) type 2D/R3, which uses the same AAVrh74 serotype as Elevidys, also died in 2025 after receiving the product in a phase 1 clinical trial (DISCOVERY; NCT01976091).^7,8 According to the FDA, this death also appeared to be related to ALF.⁹ This death lead to the FDA revoking the platform designation it had previously given to Sarepta for the AAVrh74 viral vector.^8-10 At the time, the agency also placed clinical holds on all trials currently evaluating SRP-9004 and bidridistrogene xeboparvovec (also known as SRP-9003), an investigational gene therapy product in development by Sarepta for LGMD type 2E (also known as β-sarcoglycanopathy) that also uses the AAVrh74 vector.

In July 2025, Roche, which has commercial rights for Elevidys in markets outside the United States, reported that The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) had issued an opinion recommending against conditional marketing authorization for Elevidys for patients who are ambulatory.^11,12 The CHMP’s opinion was based on data from clinical trials for Elevidys, including the pivotal phase 3 EMBARK clinical trial (NCT05096221), in which according to Roche sustained stabilization or slowing of disease progression was observed in patients who were treated with the gene therapy product. Roche noted that the trial’s primary end point was not met, but stated that statistically significant and clinically meaningful improvements compared to placebo were seen on functional outcome measures that the company referred to as “important secondary end points.”¹²

REFERENCES
1. Sarepta announces FDA’s approval of updated Elevidys prescribing information. News release. Sarepta Therapeutics, Inc. November 14, 2025. Accessed November 25, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-announces-fdas-approval-updated-elevidys-prescribing
2. FDA informs sarepta that it recommends that sarepta remove its pause and resume shipments of ELEVIDYS for ambulatory individuals with duchenne muscular dystrophy. News release. Sarepta Therapeutics, Inc. July 28, 2025. Accessed November 25, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/fda-informs-sarepta-it-recommends-sarepta-remove-its-pause-and
3. Sarepta provides safety update for ELEVIDYS and initiates steps to strengthen safety in non-ambulatory individuals with Duchenne. News release. Sarepta Therapeutics, Inc. June 15, 2025. Accessed November 25, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-provides-safety-update-elevidys-and-initiates-steps?_ga=2.73448155.831031676.1750179906-198354166.1749064502
4. Sarepta Therapeutics shares safetyupdate on Elevidys. News release. Sarepta Therapeutics, Inc. March 18, 2025. Accessed November 25, 2025. https://investorrelations.sarepta.com/static-files/0d505d91-6722-4528-aae0-1e99fcbc37e5
5. Sarepta Therapeutics provides statement on Elevidys. News release. Sarepta Therapeutics, Inc. July 18, 2025. Accessed November 25, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-provides-statement-elevidys
6. FDA recommends removal of voluntary hold for Elevidys for ambulatory patients. News release. FDA. July 28, 2025. Accessed November 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-recommends-removal-voluntary-hold-elevidys-ambulatory-patients
7. Sarepta Therapeutics provides statement on Elevidys. News release. Sarepta Therapeutics Inc. July 18, 2025. Accessed November 25, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-provides-statement-elevidys
8. Philippidis A. StockWatch: Sarepta shares nosedive after LGMD gene therapy patient dies. Genetic Engineering & Biotechnology News. July 20, 2025. Accessed November 25, 2025. https://www.genengnews.com/topics/genome-editing/stockwatch-sarepta-shares-nosedive-after-lgmd-gene-therapy-patient-dies/
9. FDA requests Sarepta Therapeutics suspend distribution of Elevidys and places clinical trials on hold for multiple gene therapy products following 3 deaths. News release. FDA. July 18, 2025. Accessed November 25, 2025. https://www.fda.gov/news-events/press-announcements/fda-requests-sarepta-therapeutics-suspend-distribution-elevidys-and-places-clinical-trials-hold
10. U.S. FDA grants platform technology designation to the viral vector used in SRP-9003, Sarepta’s investigational gene therapy for the treatment of limb girdle muscular dystrophy type 2E/R4. News release. Sarepta Therapeutics Inc. June 4, 2025. Accessed November 25, 2025. https://investorrelations.sarepta.com/news-releases/news-release-details/us-fda-grants-platform-technology-designation-viral-vector-used
11. Roche provides regulatory update on Elevidys™ gene therapy for Duchenne muscular dystrophy in the EU. News release. Roche. July 24, 2025. Accessed November 25, 2025. https://www.roche.com/media/releases/med-cor-2025-07-25
12. DMD gene therapy Elevidys dealt another blow, this time from EU panel. News article. Matthew Dennis. FirstWord PHARMA. July 25, 2025. Accessed November 25, 2025. https://firstwordpharma.com/story/5983866