Patient dies after receiving gene therapy for Duchenne muscular dystrophy

A 16-year-old has died from acute liver failure after receiving Elevidys, a gene therapy for Duchenne muscular dystrophy (DMD).

DMD is a rare neuromuscular disorder, mostly affecting boys, caused by mutations in the dystrophin gene. The dystrophin protein is essential in strengthening and connecting muscle fibres. DMD causes progressive weakening of the muscles leading to a fatal decline in muscle integrity. Elevidys, a one-time adeno-associated virus-based gene therapy, delivers microdystrophin, a shortened form of the dystrophin gene. Sarepta Therapeutics, the company that developed the gene therapy, issued a statement that the patient suffered acute liver failure following treatment.

'We are collecting additional information, but based on the current information from the treating physician, including the time since treatment and the clinical course, we cannot rule out the possibility that Elevidys was a contributing factor,' a spokesperson for Sarepta Therapeutics told Fierce Pharma.

Liver toxicity has been identified as a risk of gene therapies that use adeno-associated viral vectors to deliver modified genes. Two deaths due to acute liver failure were reported, following the delivery of Zolgensma, a gene therapy for spinal muscular atrophy developed by Novartis. Zolgensma was licensed for use by the NHS in March 2021 (see BioNews 1098 and 1087).

Elevidys has been approved by the US Food and Drug Administration (FDA) (see BioNews 1196) but remains under review in the UK and Europe (see BioNews 1271). To date, more than 800 people with DMD have received Elevidys, and this is the first death linked to this gene therapy.

In an earlier safety analysis shared by Sarepta Therapeutics, eight cases of liver abnormalities were observed in a 156-patient cohort, all of which were resolved after 90 days. After the death, Sarepta Therapeutics stated: 'The event has been reported to the relevant health authorities and [we] intend to update the prescribing information to appropriately represent this event.' The FDA assigns boxed warnings – the highest safety-related warning – to drugs, which are intended to highlight the drug's major risks. The FDA has assigned such a warning to Zolgensma, but not Elevidys as of yet.

Sarepta Therapeutics reported that the patient had a recent cytomegalovirus infection, which is a common virus that can lead to serious health issues in individuals with compromised immune systems. In some cases, this can lead to liver damage, and the patient's physician suggested that the viral infection may have been a contributing factor. Experts recommend stringent monitoring for preexisting liver conditions before commencing with gene therapy.

The death raises questions about the benefit-risk of Elevidys treatment, as the gene therapy failed to meet the primary and secondary endpoints of a late-stage clinical trial published in Nature Medicine. However, some improvements were noted between untreated and treated children, and analysts have described the long-term benefits as encouraging. Families affected by DMD have criticised Sarepta Thearpeutics for the high cost of treatment and the lack of clinically meaningful improvements in clinical trials.

Patient advocacy group Parent Project Muscular Dystrophy issued a statement that noted 'This tragic loss highlights the urgent need to fully understand the risks associated with gene therapy in our current therapeutic landscape to ensure patient safety.'