Sarepta Provides Safety Update for AAV-Based Gene Therapy and Initiates Steps to Strengthen Safety in Non-Ambulatory Individuals with Duchenne

Sarepta Therapeutics has announced a second patient death linked to its Duchenne muscular dystrophy (DMD) gene therapy, Elevidys. The fatality, a 15-year-old non-ambulatory patient in the Phase III ENVISION trial, was due to acute liver failure, a known side effect of adeno-associated virus (AAV)-based gene therapies. This follows a similar death reported in March, also in a non-ambulatory patient.

Key Details and Sarepta’s Response:

• Second Fatality: A 15-year-old patient in the Phase III ENVISION trial died from acute liver failure. This is the second such death following Elevidys treatment, both occurring in non-ambulatory patients.
• Known Side Effect: Acute liver failure is a recognized risk of AAV-based gene therapies, which are the current standard for gene delivery. The liver is particularly susceptible due to its role in processing viral vectors, leading to a concentrated immune response against the AAV capsid or transduced cells.
• Suspension of Guidance: Sarepta has suspended its 2025 revenue guidance and will provide an update at its second-quarter earnings call.
• Safety Initiatives:

  • An independent group of experts will consider an “enhanced immunosuppression regimen” for Elevidys to mitigate the AAV-related immune response.
  • Elevidys shipments for non-ambulatory patients are temporarily halted until a new immunosuppressive approach is established, specifically to address the heightened risk profile observed in this patient population with AAV delivery.
  • Sarepta is discussing adding the immunosuppressant Sirolimus to the regimen with the FDA, as preclinical data suggests it may help manage liver enzyme elevations without affecting Elevidys’ function. However, Sirolimus itself carries risks, including increased infection risk, underscoring the delicate balance in managing AAV-induced toxicity.

• ENVISION Trial Suspension: Dosing in the Phase III ENVISION study, which is crucial for converting Elevidys’ accelerated approval to full approval, has been suspended to allow for protocol amendments and implementation of improved immunosuppressive regimens, aiming to enhance the safety profile of the AAV vector delivery.
• Discussions with Patient Community: Sarepta plans to discuss the death with the DMD patient community at the upcoming Parent Project Muscular Dystrophy conference, which begins June 19 in Las Vegas, addressing concerns about the safety of AAV gene therapies.

Industry and Market Impact:

• Market Reaction: Sarepta’s shares dropped 41% in pre-market trading following the announcement, settling at $21.01.
• Analyst Concerns: Analysts, while calling the death “unsurprising” as part of the broader AAV risk—a known challenge in the gene therapy field—express concerns about additional deaths and potential market withdrawal for Elevidys, particularly for non-ambulatory patients. However, they generally believe the approval for ambulatory patients is unlikely to be pulled.
• Broader Gene Therapy Implications: This latest fatality is seen as reinforcing the unpredictability of safety events with gene therapies, especially those using AAVs, potentially increasing regulatory scrutiny for other investigational DMD gene therapies and casting a “cold winter” over the gene therapy space.

Sarepta emphasizes its commitment to patient safety and is moving quickly to address the issue with the FDA and the patient community. The company needs to demonstrate a revised safety profile for its AAV-based therapy to mitigate the risks and uncertainties surrounding Elevidys’ future.