19 July 2025
Category: Drug Safety Alert / Gene Therapy Safety Update
Written by: Pharmacally Medical News Desk
Sarepta Therapeutics has been developing investigational gene therapies based on AAVrh74 vector technology for several forms of muscular dystrophy. One such therapy, SRP-9004, is being tested for limb-girdle muscular dystrophy (LGMD), while another product, Elevidys (SRP-9001), is already approved under an accelerated pathway for certain patients with Duchenne muscular dystrophy (DMD). Both therapies use the same AAVrh74 platform to deliver genetic material to muscle tissue.
On July 18, 2025, Sarepta reported that a third patient died due to acute liver failure, and the first from the ongoing clinical trial for its limb-girdle muscular dystrophy. The patient, a 51-year-old adult with LGMD, was enrolled in a Phase 1 study and received SRP-9004 approximately 80 days before the fatal event. According to Sarepta, the patient was non-ambulatory and had pre-existing comorbidities, but the direct cause of death was liver failure, raising serious concerns about the safety of the gene therapy.
This is the third reported death related to Sarepta’s AAVrh74-based gene therapies in recent months. The first two cases involved non-ambulatory teenage patients with DMD who had received Elevidys. Both patients also died from acute liver failure, one in March and the second in June this year, prompting Sarepta earlier to pause dosing in non-ambulatory patients and apply additional monitoring strategies for liver function.
Sarepta stated it had been monitoring all patients closely and was working with experts to investigate the cause of liver injury. They disclosed the third death only after it occurred, and this comes shortly after announcing internal changes, including restructuring and reduced investment in their LGMD program. While Sarepta claimed the patient had pre-existing conditions, the repeated nature of liver injury across different studies using the same AAVrh74 vector raised red flags.
FDA’s Actions and Instructions
In immediate response to the third fatality, the U.S. FDA has taken decisive action, effective July 18, 2025. The agency has
- Placed all Sarepta AAVrh74 therapeutic clinical trials, including the LGMD study, on full clinical hold.
- Requested (informally) that Sarepta voluntarily suspend all shipments of Elevidys, even though the latest death was not in an Elevidys‑treated patient
- Revoked the company’s AAVrh74 platform technology designation, citing insufficient evidence to ensure safe, multi‑indication use of the platform
FDA Commissioner Dr. Marty Makary emphasized quick action to protect patient safety, stating the risks now outweigh the benefits, particularly for non‑ambulatory patients.
Dr. Vinay Prasad, head of CBER, confirmed the trials were halted due to “unreasonable and significant risk of illness or injury.”
Now Where Sarepta Stands:
Sarepta has paused use of Elevidys in non-ambulatory patients earlier after the second death only, but they resisted full suspension of Elevidys shipments and continue to make it available for ambulatory patients under existing approvals. The company is in discussions with the FDA to update safety labels and may introduce a black‑box warning for liver toxicity and new liver monitoring protocols, such as the use of immunosuppressive agents like sirolimus. Further patient enrollment across AAVrh74 studies is currently halted.
Summary and Implications
Three patients have now died of acute liver failure linked to Sarepta’s AAVrh74 gene therapies: two Elevidys DMD patients (teenagers, non-ambulatory) and one SRP‑9004 LGMD patient (adult).
FDA actions (July 18, 2025): clinical holds on LGMD trials, platform designation revoked, and shipment suspension request for Elevidys.
Sarepta’s stance: continues Elevidys for ambulatory DMD patients, pauses non-ambulatory shipments, and plans updated label and mitigation measures.
Implications
Safety of therapies based on AAVrh74 vector technology in nonambulatory patients is now clearly established.
Ongoing risk investigations may extend to ambulatory DMD patients.
Regulatory approval prospects for future AAVrh74-based therapies are critically impaired.
Closing Remark
This third death due to acute liver failure following use of Sarepta’s AAVrh74-based gene therapies signals a serious safety concern. While gene therapies hold promise, repeated adverse events with fatal outcomes call for extreme caution, especially in vulnerable populations like non-ambulatory patients. Regulatory agencies and companies must prioritize transparent reporting, patient safety, and re-evaluation of risk, particularly when using viral vectors like AAV that may trigger immune-mediated liver injury. Until safety concerns are fully addressed, further clinical use of AAVrh74-based gene therapies remains on hold.
References
FDA Investigating Deaths Due to Acute Liver Failure Following Treatment with Sarepta’s AAVrh74 Gene Therapies, US Food and Drug Administration, 18 July 2025, https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-deaths-due-acute-liver-failure-following-treatment-sareptas-aavrh74-gene-therapies/
FDA Suspends Sarepta’s Gene Therapy Trials after Deaths; But Company Declines ELEVIDYS Shipment Halt, Nasdaq, July 19 2025, https://www.nasdaq.com/articles/fda-suspends-sareptas-gene-therapy-trials-after-deaths-company-declines-elevidys-shipment/
Elvidys Update: Parent Project Muscular Dystrophy, 18 July 2025, https://www.parentprojectmd.org/elevidys-update/
FDA Shuts Down Sarepta’s Distribution of Gene Therapy Elevidys Following Patient Deaths, Neurology Live, 18 July 2025, https://www.neurologylive.com/view/third-patient-death-leads-significant-concerns-sarepta-gene-therapy-program?utm_source=chatgpt.com
