On Jun. 22, 2023, the U.S. Food and Drug Administration (FDA) approved Sarepta Therapeutics’s Elevidys, the first gene therapy for the treatment of pediatric patients 4 through 5 years of age with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene who do not have a pre-existing medical reason preventing treatment with this therapy.

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 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, learning disabilities/difficulties, heart issues as a result of impact on heart muscle functioning, 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. Most current treatment approaches address the symptoms of the disease, but not its underlying genetic cause. Treatments include corticosteroid medications to slow down the progression of muscle weakness, stretching and exercise programs, and use of equipment such as braces or a wheelchair as walking becomes more difficult. Antisense oligonucleotides (ASOs) facilitate exon skipping for specific DMD gene mutations, but the ASOs can only address a minority of the gene mutations and require repeated administration.  

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 approved 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 generally provides patients earlier access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

A clinical benefit of Elevidys, including improved motor function, has not been established. As a condition of approval, the FDA is requiring the company to complete a clinical study to confirm the drug’s clinical benefit. The required study is designed to assess whether Elevidys improves physical function and mobility in ambulatory DMD patients with a confirmed mutation in the DMD gene. The study is ongoing and fully enrolled. The agency will review the data from this trial as quickly as possible to consider if further action, such as a revised indication or withdrawal of Elevidys, may be necessary.

The most commonly reported side effects by individuals who received Elevidys were vomiting, nausea, acute liver injury, pyrexia (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.