Controversial Gene Therapy Wins FDA Approval for Duchenne Muscular Dystrophy

The FDA granted accelerated approval to delandistrogene moxeparvovec (Elevidys), the first gene therapy for Duchenne muscular dystrophy, the agency announced Thursday.

The adeno-associated virus-based gene therapy is a one-time treatment designed to treat the underlying genetic cause of Duchenne muscular dystrophy. It is approved for ambulatory Duchenne pediatric patients ages 4 to 5 years with a confirmed mutation in the DMD gene.

Duchenne muscular dystrophy is characterized by a mutation that leads to a lack of dystrophin and muscle loss. It affects about one in 3,300 boys and has no known cure. Delandistrogene moxeparvovec delivers a gene that codes for a shortened form of dystrophin — a novel, engineered protein called micro-dystrophin — to help preserve muscle.

“Today’s approval addresses an urgent unmet medical need and is an important advancement in the treatment of Duchenne muscular dystrophy, a devastating condition with limited treatment options, that leads to a progressive deterioration of an individual’s health over time,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, in the FDA press release.

The agency’s decision was based on data submitted to the FDA by Sarepta Therapeutics, including clinical studies that established expression of the micro-dystrophin protein in skeletal muscle, in addition to biologic and empirical evidence.

Clinical benefit of the gene therapy, including improved motor function, has not been established, the FDA said. Delandistrogene moxeparvovec was approved through the accelerated approval pathway, a pathway for drugs for serious or life-threatening diseases with an unmet medical need. Under this pathway, treatments must show an effect on a surrogate endpoint that’s reasonably likely to predict clinical benefit. The surrogate endpoint in this case was micro-dystrophin.

Acute serious liver injury, immune-mediated myositis, and myocarditis occurred in patients treated with delandistrogene moxeparvovec. The most common adverse reactions in clinical studies were vomiting, nausea, liver function test increases, pyrexia, and thrombocytopenia. The treatment is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene, Sarepta said.

In May, FDA advisors narrowly supported delandistrogene moxeparvovec, but in briefing documents leading up to the advisory committee meeting, FDA reviewers noted that no epidemiologic or pathophysiologic evidence of micro-dystrophin’s function existed.

As a condition of approval, the FDA will require Sarepta to complete a clinical study confirming the drug’s clinical benefit. The confirmatory EMBARK trial is ongoing and is designed to assess whether delandistrogene moxeparvovec improves physical function and mobility in ambulatory Duchenne patients.

“The agency will review the data from this trial as quickly as possible to consider if further action, such as a revised indication or withdrawal of Elevidys, may be necessary,” the FDA stated.

To date, four exon-skipping drugs — including three from Sarepta — have received accelerated FDA approval for Duchenne patients with specific DMD mutations. The clinical benefit of these exon-skipping drugs has not been verified in confirmatory trials.