The FDA (Elevidys) gene therapy for Duchenne muscular dystrophy on Thursday to include ambulatory or non-ambulatory patients ages 4 years and older with a confirmed DMD gene mutation.
In June 2023, delandistrogene moxeparvovec received accelerated approval for ambulatory Duchenne pediatric patients ages 4 to 5 years. The FDA's action on Thursday converted the agency's decision from accelerated to traditional approval for ambulatory Duchenne patients ages 4 and up and granted accelerated approval for non-ambulatory Duchenne patients in that age group.
This "broadens the spectrum of patients with Duchenne muscular dystrophy eligible for this therapy, helping to address the ongoing, urgent treatment need for patients with this devastating and life-threatening disease," said Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research.
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.
Delandistrogene moxeparvovec delivers a gene that codes for a shortened form of dystrophin -- a novel, engineered protein called micro-dystrophin -- to help preserve muscle, administered as a single-dose adeno-associated virus (AAV)-based gene transfer therapy.
Under the , 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.
In May 2023, FDA's advisors narrowly supported delandistrogene moxeparvovec. But in leading up to the advisory committee meeting, FDA staff members said no epidemiologic or pathophysiologic evidence of micro-dystrophin's function existed.
As a condition of accelerated approval last June, the FDA required drugmaker Sarepta Therapeutics to complete a study confirming the clinical benefit of delandistrogene moxeparvovec. In October 2023, Sarepta said the confirmatory EMBARK trial of improvement on the North Star Ambulatory Assessment of motor function, but showed statistically significant results on all key secondary endpoints, including time to rise (P=0.0025) and the 10-meter walk test (P=0.0048).
The FDA's decision this week was based on the "totality of the evidence" from two placebo-controlled and two open-label studies, including EMBARK and the open-label trial of Duchenne patients ages 2 years and older. The agency found the observations on the secondary and exploratory endpoints "to be compelling and to indicate clinical benefit compared to placebo," noting there was "substantial evidence of effectiveness to support traditional approval."
Several secondary endpoints were above minimal clinical important difference thresholds, Marks wrote in his . However, the statistical significance of EMBARK'S secondary endpoints was questioned by the agency's Office of Clinical Evaluation, which maintained that traditional approval.
The FDA's decision is "a significant step forward in the fight against Duchenne muscular dystrophy," said Barry Byrne, MD, PhD, chief medical advisor of the Muscular Dystrophy Association, in a . "The full approval for all ambulant patients and accelerated approval for all non-ambulant patients is not only a scientific accomplishment but a major source of hope for countless families affected by this relentless disease."
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, .
The trial, a confirmatory placebo-controlled study of non-ambulatory and older ambulatory individuals with Duchenne, is underway.