A young person with Duchenne muscular dystrophy died after treatment with the recently approved gene therapy delandistrogene moxeparvovec (Elevidys), Sarepta Therapeutics said last week, adding that the patient had experienced acute liver failure.
Testing showed he also had a recent cytomegalovirus (CMV) infection, which was a possible contributing factor, according to the treating physician.
“Although it is not a new safety signal and the benefit-risk of Elevidys remains positive, acute liver failure leading to death represents a severity of acute liver injury not previously reported for the treatment, which to date has been used on more than 800 patients in clinical trials or as a prescribed therapy," Sarepta said.
Medpage Today reports that acute liver injury is a possible side effect of delandistrogene moxeparvovec and other adeno-associated virus (AAV)-mediated gene therapies and is highlighted in the treatment’s prescribing information.
Duchenne muscular dystrophy is characterised by a mutation in the DMD gene that leads to a lack of dystrophin and muscle loss. It affects about one in 3 300 boys.
Delandistrogene moxeparvovec delivers a gene that codes for a shortened form of dystrophin – an engineered protein called micro-dystrophin – to help preserve muscle.
After an initial accelerated approval decision in 2023, delandistrogene moxeparvovec received full FDA approval in June 2024 to treat ambulatory or non-ambulatory patients aged four years and older with a confirmed DMD gene mutation.
As a condition of accelerated approval, the agency required Sarepta to complete a study confirming the drug’s clinical benefit.
Several months later, in October 2023, Sarepta said the confirmatory EMBARK trial did not meet its primary endpoint.
In his decisional memo, however, Peter Marks, MD, PhD, of the FDA’s Centre for Biologics Evaluation and Research, said that full approval was supported “based on the totality of the evidence” for delandistrogene moxeparvovec, and that several secondary endpoints in EMBARK and other studies were above minimal clinical important difference thresholds.
The statistical significance of EMBARK’S secondary endpoints was questioned by the FDA’s Office of Clinical Evaluation, which maintained that the study did not support traditional approval.
Published data from EMBARK subsequently confirmed that while the gene therapy missed its primary endpoint, it showed small differences in other functional outcomes.
Deaths have occurred with other gene therapies for rare diseases. In 2024, Pfizer reported a death during in a phase II study of fordadistrogene movaparvovec, an investigational agent for Duchenne muscular dystrophy; the company has since discontinued the treatment.
In 2022, two children with spinal muscular atrophy died of acute liver failure within weeks of taking onasemnogene abeparvovec (Zolgensma).
See more from MedicalBrief archives:
FDA accelerated approval for Duchenne drug questioned
FDA preliminary nod for muscular dystrophy gene therapy