FDA probing deaths with DMD gene therapy Elevidys

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FDA probing deaths with DMD gene therapy Elevidys

The FDA has launched a formal investigation into two reports of fatal acute liver failure in patients treated with Sarepta and Roche's Duchenne muscular dystrophy (DMD) gene therapy Elevidys.

The two deaths – one reported in March and the second earlier this month – both involved non-ambulatory DMD patients and "appear to be related to treatment with Elevidys" (delandistrogene moxeparvovec), according to the US regulator.

The fatalities occurred in two boys who were hospitalised with acute liver failure less than two months after treatment with the one-shot gene therapy. Sarepta and Roche – which has ex-US rights to the therapy – have halted treatment with Elevidys for non-ambulatory DMD patients and also paused clinical trials while they look into risk-mitigation measures.

That includes the ENVISION clinical trial (SRP-9001-303) in non-ambulatory as well as older ambulatory individuals, which is under review to see if it needs protocol updates.

In a statement, the FDA said it is "evaluating the need for further regulatory action" in its investigation, noting that prescribing information for Elevidys already includes information on the risk of acute serious liver injury with the therapy, but "does not include warnings regarding liver failure or death."

Elevidys has been given full approval to treat ambulatory patients with DMD, with an accelerated approval in non-ambulatory patients, and more than 900 people have been treated with the gene therapy in clinical trials and commercial settings.

Liver damage is a well-recognised complication of gene therapies based on adeno-associated virus (AAV) vectors, and other drugs – including Novartis' spinal muscular atrophy (SMA) treatment Zolgensma (onasemnogene abeparvovec) and Astellas' X-linked myotubular myopathy therapy AT132 – have been associated with deaths due to acute liver failure.

After news of the second death was announced, Sarepta said it planned to set up an expert committee with representation from patients and healthcare professionals to look into ways to minimise the risk of treatment.

One way to reduce the risk is to administer immunosuppressive drugs like corticosteroids to dampen down inflammation of the liver (hepatitis) if biomarkers of liver damage rise after treatment, and the company has said it is hoping to develop an 'enhanced' immunosuppression regimen for Elevidys patients, including the possible use of sirolimus alongside corticosteroids.

Patient advocacy group Parent Project Muscular Dystrophy (PPMD) said the deaths are a "devastating reminder of both the promise and the complexity of this emerging therapeutic landscape."

It added: "As we mourn alongside the community, we must also work toward a better understanding of the risks involved and improvement of safety monitoring protocols to ensure that the well-being of every individual remains top priority."