FDA expands approval of gene therapy for patients with Duchenne muscular dystrophy

Today, the US Food and Drug Administration extended 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 DMD gene.

Elevidys was previously approved under accelerated approval for ambulatory individuals 4 to 5 years of age with DMD with a confirmed mutation in the DMD gene. With today’s action, Elevidys received traditional approval for ambulatory individuals 4 years of age and older with DMD with a confirmed mutation in DMD gene and accelerated approval in non-ambulatory individuals 4 years of age and older with DMD with a confirmed mutation in 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 expands the spectrum of patients with Duchenne muscular dystrophy eligible for this therapy, helping to address the ongoing and urgent need for treatment for patients with this devastating and life-threatening disease,” said Peter Marks, MD, Ph. D., director. of 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 that worsens over time, leading to weakness and wasting of the body’s muscles. The disease is caused by a faulty gene that results in an abnormality or lack of dystrophin, a protein that helps keep muscle cells intact.

As a result of this genetic defect, individuals with DMD may have symptoms such as difficulty walking and running, frequent falls, fatigue, and learning disabilities/difficulties. They may also experience heart problems as a result of the effect on heart muscle function and breathing problems due to weakening of the respiratory muscles involved in lung function. Symptoms of muscle weakness associated with DMD usually begin in childhood, often between the ages of 3 and 6.

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

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

Elevidys was originally approved in June 2023 through the accelerated approval pathway, under which the FDA can approve drugs for serious or life-threatening diseases when there is an unmet medical need and the drug is shown to have an effect on a surrogate endpoint that it is reasonably. is likely to predict clinical benefit to patients (by 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 has reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit. This route may allow earlier approval while the company conducts clinical trials to verify the anticipated clinical benefit.

Data supporting traditional approval

The FDA granted today’s approval based on an evaluation of the 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 micro-dystrophin expression in skeletal muscle and to assess the effect of Elevidys on patients’ total score on the North Star Ambulatory Assessment (NSAA) – a commonly used scale to assess motor function in men with DMD who are able to walk. In another study, the main efficacy outcome measure was the assessment of the effect of Elevidys on physical function as assessed by the NSAA total score. Primary secondary outcome measures were assessment of micro-dystrophin expression in skeletal muscle, time to stand up from the floor, and 10m walk/run time. Additional performance outcome measures included time to walk/run 100 meters and time to climb four flights of stairs.

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

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

Expedited Approval Supporting Data

In granting accelerated approval for nonambulatory individuals 4 years of age and older, the FDA considered the totality of the evidence, including clinical data in ambulatory individuals from a study at 4 to 7 years of age, as well as from a study at 4 – in 5-year-olds showing 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 of micro-dystrophin are likely to predict clinical benefit in the non-ambulatory population. This conclusion, together with the evidence that Elevidys increases micro-dystrophin levels, provides substantial evidence of effectiveness to support accelerated approval in non-ambulatory individuals at least 4 years of age with DMD given the serious nature of the disease and the unmet medical scope. needs 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 DMD gen 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 outpatients treated with the marketed product. A modest amount of safety data for non-ambulatory individuals was submitted in the context of an ongoing randomized clinical trial; safety data in non-ambulatory individuals are limited, given the number of non-ambulatory individuals included in the trial and treated with the marketed product to date.

The most common side effects reported by individuals taking Elevidys were vomiting, nausea, acute liver damage, fever, and thrombocytopenia (abnormally low number of platelets in the blood). Patients’ liver function should be monitored before treatment with Elevidys and weekly for the first three months after treatment. Patients taking Elevidys may also be at risk for severe immune-mediated myositis (inflammation of the muscles). In addition, myocarditis (inflammation of the heart muscle) and increased troponin-I (a heart protein found in the blood after damage to the heart muscle) have been observed after the use of Elevidys in clinical trials. Troponin-I levels should be monitored before Elevidys administration and weekly for the first month after treatment.

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

Approximate Information

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