Tuesday, July 16, 2024

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

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Duchenne muscular dystrophy (DMD) treatment with Elevidys (delandistrogene moxeparvovec-rokl) has received expanded approval from the U.S. Food and Drug Administration (FDA) to include both ambulatory and non-ambulatory individuals aged 4 years and older with a confirmed mutation in the DMD gene.

This therapy was previously approved under accelerated approval for ambulatory individuals aged 4 through 5 years. The latest action grants traditional approval for ambulatory individuals aged 4 and older and accelerated approval for non-ambulatory individuals within the same age range. This decision was based on the overall evidence, considering the product’s potential risks, the severe nature of DMD, 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 severe genetic condition characterized by progressive muscle weakness and wasting, leading to significant disability. It results from a defective gene that causes abnormalities in, or the absence of, dystrophin, a crucial protein for muscle cell integrity.

Symptoms often begin in childhood, typically between ages 3 and 6, and can include difficulties in walking and running, frequent falls, fatigue, and learning disabilities. As the disease progresses, patients may experience heart problems and respiratory issues due to muscle weakness. DMD primarily affects males, with an estimated prevalence of one in every 3,300 boys, and often leads to premature death in the 20s or 30s due to heart or respiratory failure.

Elevidys is a recombinant gene therapy designed to deliver a gene encoding Elevidys micro-dystrophin, a truncated version of the dystrophin protein. This micro-dystrophin contains key domains of the normal protein and is administered as a single intravenous dose. Elevidys initially received accelerated approval in June 2023, allowing for earlier approval based on a surrogate endpoint likely to predict clinical benefit while ongoing clinical trials verify these benefits.

Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy: FDA Approval of Elevidys Based on Robust Clinical Data

The FDA’s traditional approval of Elevidys was based on data from two double-blind, placebo-controlled studies and two open-label studies, involving a total of 218 male patients with a confirmed DMD gene mutation. These studies aimed to evaluate the expression of micro-dystrophin in skeletal muscle and assess the therapy’s impact on the North Star Ambulatory Assessment (NSAA) scores, a scale used to rate motor function in ambulatory males with DMD.

Although the primary endpoint of improvement in NSAA scores was not met, secondary and exploratory endpoints showed significant clinical benefits, including improvements in time to rise from the floor, 10-meter walk/run, time to ascend four steps, and creatine kinase levels. These findings led the FDA to determine that Elevidys provides substantial evidence of effectiveness to support its traditional approval for ambulatory individuals aged 4 and older, except for those with deletions in exon 8 and/or exon 9 of the DMD gene.

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For the accelerated approval of Elevidys in non-ambulatory individuals aged 4 and older, the FDA considered data from clinical studies in ambulatory individuals, indicating a correlation between micro-dystrophin levels and clinical outcomes. Given the similar mechanism of action for both ambulatory and non-ambulatory populations, the FDA concluded that increased micro-dystrophin levels are reasonably likely to predict clinical benefit in non-ambulatory patients. A confirmatory randomized, controlled clinical trial in the non-ambulatory population is ongoing.

The safety of Elevidys was evaluated based on data from 156 male patients with a confirmed DMD gene mutation across four clinical studies. Common side effects included vomiting, nausea, acute liver injury, fever, and thrombocytopenia. Patients should have their liver function monitored before and after treatment. There is also a risk of severe immune-mediated myositis and myocarditis, with troponin-I levels to be monitored before and after administration.

Overall, the expanded approval of Elevidys marks a significant advancement in the treatment of DMD, providing broader access to a potentially life-changing therapy for a greater number of patients. The FDA’s decision underscores the importance of continued research and development to address the unmet needs of those affected by this debilitating disease.

Resource: Food and Drug Administration, June 20, 2024

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