FDA Expands Approval of Gene Therapy for Duchenne Muscular Dystrophy Patients

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

Elevidys has already been approved under accelerated approval for ambulatory individuals aged 4 to 5 years with DMD with a confirmed DMD gene mutation. With today’s action, Elevidys has received traditional approval in outpatient individuals ages 4 and older with DMD with a confirmed mutation in the DMD gene and accelerated approval in non-ambulatory individuals aged 4 years and older with DMD with a confirmed mutation in the DMD embarrassed. In making this decision, the FDA considered all of the evidence, including the potential risks associated with the product, the potentially life-threatening and debilitating nature of the disease, and the urgent unmet medical need.

“Today’s approval expands the spectrum of Duchenne muscular dystrophy patients eligible for this treatment, helping to meet the need for continued and urgent treatment of patients with this devastating and life-threatening disease,” said Peter Marks, MD, Ph.D., Director of the FDA’s Center for Biologics Evaluation and Research. “We remain steadfast in our commitment to helping advance safe and effective treatments for patients who desperately need them.” »

Duchenne muscular dystrophy is a rare and serious genetic disorder that worsens over time, causing weakness and atrophy of the body’s muscles. The disease is caused by a faulty gene that causes abnormalities or a lack of dystrophin, a protein that helps keep the body’s muscle cells intact.

Due to this genetic abnormality, people with DMD may experience symptoms such as difficulty walking and running, frequent falls, fatigue, and learning disabilities/difficulties. They may also suffer from heart problems due to the impact 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 ages 3 and 6.

DMD primarily affects men and, in rare cases, can affect women. About one in 3,300 boys is 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 introduce a gene into the body that leads to the production of Elevidys micro-dystrophin, a shortened protein (138 kDa, compared to the 427 kDa dystrophin protein in normal muscle cells) that contains selected domains of dystrophin. protein found in normal muscle cells. The product is administered in a single intravenous dose.

Elevidys was initially approved in June 2023 through the accelerated approval pathway, under which the FDA can approve drugs for serious or life-threatening conditions when there is an unmet medical need and it is demonstrated that the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients (improvement in how patients feel or function, or whether they survive longer), or an effect on an 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 may allow for earlier approval, while the company conducts clinical trials to verify the anticipated clinical benefit.

Data Supporting Traditional Endorsement

The FDA granted today’s approval based on an evaluation of data submitted by the sponsor. The effectiveness 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 pathogenic mutation in the gene DMD.

In one of the studies, efficacy outcome measures included assessing microdystrophin expression in skeletal muscle and assessing the effect of Elevidys on patients’ total score on the North Star Ambulatory Assessment ( NSAA) – a scale commonly used to assess motor function in men with DMD who are able to walk. In another study, the primary efficacy endpoint was to assess the effect of Elevidys on physical function, as assessed by the NSAA total score. The main secondary outcomes were to assess micro-dystrophin expression in skeletal muscle, time to get up from the ground and 10 meter walk/run time. Additional efficiency outcome measures included 100-meter walk/run time and time to climb four steps.

While the large randomized study of Elevidys failed to meet its primary statistical endpoint of improvement over placebo in the NSAA, the FDA found that observations regarding secondary endpoints and Exploratory endpoints were convincing and indicated clinical benefit compared to placebo. These metrics include improvements in time taken to get up from the ground, 10 meter walk/run, time taken to climb four steps, and creatine kinase levels.

Based on the totality of evidence, the FDA has determined that the available evidence verifies the clinical benefit of the product for its initial indication, which was initially approved in June 2023 under accelerated approval, and provides evidence substantial evidence of efficacy to support traditional approval of Elevidys in ambulatory individuals. 4 years and over with a confirmed mutation in the DMD gene except in those with a deletion in exon 8 and/or exon 9 in the DMD gene, in whom its use is contraindicated. Insufficient safety data is currently available to support the use of Elevidys in individuals younger than 4 years of age.

Data supporting accelerated approval

In granting accelerated approval to non-ambulatory individuals ages 4 and older, the FDA considered the body of evidence, including clinical data in ambulatory individuals from a study of children ages 4 to 7 years, as well as a study carried out on children aged 4 and over. – in children aged 5 years 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 has determined that an increase in microdystrophin levels is reasonably likely to predict clinical benefit in the population. non-ambulatory. This finding, along with evidence that Elevidys elevates microdystrophin levels, provides substantial evidence of its effectiveness to support accelerated approval in non-ambulatory individuals aged at least 4 years with DMD, given the severe nature of illness and the extent of unmet medical problems. needed 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 the evaluation of 156 male patients with a confirmed mutation of DMD gene who received the product in four clinical studies, including one completed open-label study, one ongoing open-label study, and two studies including a double-blind, placebo-controlled period. No new safety concerns appear to have been identified in the ambulatory population treated with the marketed product. A modest amount of safety data in non-ambulatory individuals has been 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 product marketed to date.

The most common side effects reported by people who received 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 receiving Elevidys may also be at risk of severe immune-mediated myositis (muscle inflammation). Additionally, myocarditis (inflammation of the heart muscle) and elevations of troponin-I (a heart protein present in the blood after heart muscle injury) have been observed following the use of Elevidys in clinical trials. Troponin-I levels should be monitored before administration of Elevidys and weekly for the first month following treatment.

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

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