FDA Approves First Gene Therapy Treatment for Duchenne Muscular Dystrophy

The U.S. Food and Drug Administration recently approved Elevidys, the first gene therapy for the treatment of pediatric patients four through five years of age with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene who do not have a preexisting medical reason preventing treatment with this therapy. 

“Today’s approval addresses an urgent unmet medical need and is an important advancement in the treatment of Duchenne muscular dystrophy, a devastating condition with limited treatment options, that leads to a progressive deterioration of an individual’s health over time,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “The FDA remains committed to facilitating the development of innovative new therapies to reduce the impact of debilitating diseases and to improve outcomes and quality of life for those affected.”

What is Duchenne muscular dystrophy?

DMD is a rare and serious genetic condition that 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 the 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 an impact on heart muscle functioning, and 

• breathing problems due to the weakening of respiratory muscles involved in lung function. 

Symptoms of muscle weakness associated with DMD typically begin in childhood, often between three to six years of age. DMD mainly affects males and in rare cases may affect females. 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 the 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.  

What is Elevidys? How does it work?

Elevidys is a recombinant gene therapy designed to deliver into the body a gene that leads to the 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 to Sarepta Therapeutics, Inc. Via the pathway, the FDA approves 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 or an effect on a clinical endpoint that can be measured earlier than irreversible morbidity that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefits. The Accelerated Approval pathway generally provides patients earlier access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The FDA granted approval based on an evaluation of data submitted by the sponsor. In one study which involved two parts, individuals in part one—which was randomized, double-blind, and placebo-controlled—were treated with either Elevidys or placebo and followed for 48 weeks. In part two of the study, individuals who received a placebo during part one were treated with Elevidys, and individuals treated with Elevidys during part one received a placebo. All individuals were followed for an additional 48 weeks. 

The accelerated approval of Elevidys was based on data from the randomized clinical trial that established that Elevidys increased the expression of the Elevidys micro-dystrophin protein observed in Elevidys-treated individuals aged four to five years with DMD. The FDA concluded that the data submitted by the applicant demonstrated that an increase in this surrogate endpoint (expression of Elevidys micro-dystrophin) is reasonably likely to predict clinical benefit in individuals four to five years of age with DMD who do not have significant preexisting antibody titers against the Adeno-associated virus (AAV) rh74 vector or have other contraindications based on the inclusion criteria of the clinical trials. 

In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease in affected children, and the urgent unmet medical need. 

Benefits and side effects of Elevidys gene therapy

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. Additionally, myocarditis and elevations of troponin-I have been observed following the use of Elevidys in clinical trials. Troponin-I levels should be monitored before administering Elevidys and weekly for the first month after treatment. 

- This press release was originally published on the U.S. Food and Drug Administration website