FDA Expands Approval of Gene Therapy for Patients with Duchenne Muscular Dystrophy

The U.S. Food and Drug Administration expanded the approval of Elevidys (delandistrogene moxeparvovec-rokl), a gene therapy for the treatment of Duchenne muscular dystrophy (DMD) for ambulatory and non-ambulatory individuals 4 years of age and older with DMD with a confirmed mutation in the DMD gene.

Elevidys was previously approved under accelerated approval for ambulatory individuals 4 through 5 years of age with DMD with a confirmed mutation in the DMD gene. With today’s action, Elevidys received traditional approval in ambulatory individuals 4 years of age and older with DMD with a confirmed mutation in the DMD gene, and accelerated approval in non-ambulatory individuals 4 years of age and older with DMD with a confirmed mutation in the DMD gene. In making this decision, the FDA considered the totality of the evidence, including the potential risks associated with the product, the life-threatening and debilitating nature of the disease and the urgent unmet medical need.

“Today’s approval 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, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “We remain steadfast in our commitment to help advance safe and effective treatments for patients who desperately need them.”

Duchenne muscular dystrophy is a rare and serious genetic condition which worsens over time, leading to weakness and wasting away of the body’s muscles. The disease occurs due to a defective gene that results in abnormalities in, or absence of, dystrophin, a protein that helps keep the body’s muscle cells intact.

As a result of this genetic defect, individuals with DMD may have symptoms such as trouble walking and running, falling frequently, fatigue and learning disabilities/difficulties. They may also experience heart issues as a result of the impact on heart muscle function and breathing problems due to weakening of respiratory muscles involved in lung function. Symptoms of muscle weakness associated with DMD typically begin in childhood, often between 3 to 6 years of age.

DMD mainly affects males and in rare cases may affect females. About one in every 3,300 boys are affected by this disorder. As the disease progresses, life-threatening heart and respiratory problems can occur. Although disease severity and life expectancy vary, patients often succumb to the disease in their 20s or 30s because of heart and/or respiratory failure.

Elevidys is a recombinant gene therapy designed to deliver into the body a gene that leads to production of Elevidys micro-dystrophin, a shortened protein (138 kDa, compared to the 427 kDa dystrophin protein of normal muscle cells) that contains selected domains of the dystrophin protein present in normal muscle cells. The product is administered as a single intravenous dose.

Elevidys was initially approved in June 2023 through the Accelerated Approval pathway, under which the FDA may approve drugs for serious or life-threatening diseases where there is an unmet medical need and the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (improving how patients feel or function, or whether they survive longer), or an effect on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit. This pathway can allow earlier approval, while the company conducts clinical trials to verify the predicted clinical benefit.

Data Supporting Traditional Approval

The FDA granted today’s approval based on an evaluation of data submitted by the sponsor. The efficacy of Elevidys was evaluated in two double-blind, placebo-controlled studies and two open-label studies, which enrolled a total of 218 male patients (including those who received placebo) with a confirmed disease-causing mutation in the DMD gene.

In one of the studies, the efficacy outcome measures were to evaluate expression of micro-dystrophin in skeletal muscle, and to evaluate the effect of Elevidys on the total score of patients on the North Star Ambulatory Assessment (NSAA)-a scale commonly used to rate the motor function in males with DMD who are capable of walking. In another study, the primary efficacy outcome measure was to evaluate the effect of Elevidys on physical function as assessed by the NSAA total score. Key secondary outcome measures were to evaluate expression of micro-dystrophin in skeletal muscle, time to rise from floor and time of 10-meter walk/run. Additional efficacy outcome measures included time of 100-meter walk/run and time to ascend four steps.

While the large, randomized study of Elevidys failed to meet its statistical primary endpoint of improvement versus placebo in the NSAA, the FDA found the observations regarding the secondary endpoints and exploratory endpoints to be compelling and to indicate clinical benefit compared to placebo. These endpoints include improvements in time to rise from the floor, 10-meter walk/run, time to ascend four steps and creatine kinase levels.

Based on the totality of the evidence, the FDA determined the available evidence verifies the product’s clinical benefit for its original indication, which was initially approved in June 2023 under accelerated approval, and provides substantial evidence of effectiveness to support traditional approval of Elevidys in ambulatory individuals 4 years of age and older with a confirmed mutation in the DMD gene except in those with any deletion in exon 8 and/or exon 9 in the DMD gene, in whom its use is contraindicated. An inadequate amount of safety data is available currently to support the use of Elevidys in individuals under 4 years of age.

Data Supporting Accelerated Approval

In granting accelerated approval for non-ambulatory individuals aged 4 and older, the FDA considered the totality of the evidence, including clinical data in ambulatory individuals from a study in 4- to 7-year-olds, as well as from a study in 4- to 5-year-olds indicating a correlation of Elevidys micro-dystrophin levels with clinical outcome measures. Based on the evidence and given that the mechanism of action of Elevidys is similar for ambulatory and non-ambulatory populations, the FDA determined that increased levels in micro-dystrophin is reasonably likely to predict clinical benefit in the non-ambulatory population. This conclusion, along with the evidence that Elevidys elevates micro-dystrophin levels, provides substantial evidence of effectiveness to support accelerated approval in non-ambulatory individuals at least 4 years of age with DMD considering the serious nature of the disease and the extent of unmet medical need in this group of individuals. A confirmatory randomized, controlled clinical trial in the non-ambulatory population is currently underway.

The safety of Elevidys was established based on evaluation of 156 male patients with a confirmed mutation of the DMD gene who received the product in four clinical studies, including one completed open-label study, one ongoing open-label study, and two studies that included a double-blind, placebo-controlled period. No new safety concerns appear to have been identified in the population of ambulatory individuals treated with the marketed product. A modest amount of safety data on non-ambulatory individuals was submitted in the context of an ongoing randomized clinical trial; safety data in non-ambulatory individuals is limited, given the number of non-ambulatory individuals included in the trial and treated with the marketed product to date.

The most commonly reported side effects by individuals who received Elevidys were vomiting, nausea, acute liver injury, fever and thrombocytopenia (abnormally low platelet count in the blood). Patients’ liver function should be monitored before treatment with Elevidys, and weekly for the first three months after treatment. Patients given Elevidys may also be at risk for severe immune-mediated myositis (muscle inflammation). Additionally, myocarditis (inflammation of heart muscle) and elevations of troponin-I (a heart protein found in the blood after heart muscle injury) have been observed following use of Elevidys in clinical trials. Troponin-I levels should be monitored before administration of Elevidys and weekly for the first month after treatment.

The FDA granted the approval and accelerated approval for Elevidys to Sarepta Therapeutics Inc.