The FDA has expanded the approval of delandistrogene moxeparvovec-rokl (Elevidys; Sarepta Therapeutics Inc.) for Duchenne muscular dystrophy (DMD) to include ambulatory and non-ambulatory individuals 4 years of age and older with a confirmed mutation in the DMD gene. This decision marks a significant advancement in the treatment landscape for this devastating and life-threatening disease.
Broadening Access to a Critical Therapy
In June 2023, Elevidys was initially approved under accelerated approval for ambulatory individuals aged 4 through 5 with DMD. The FDA's recent action grants traditional approval for ambulatory individuals 4 years and older and accelerated approval for non-ambulatory individuals in the same age range. Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, emphasized the importance of this expansion, stating it "broadens the spectrum of patients with Duchenne muscular dystrophy eligible for this therapy, helping to address the ongoing, urgent treatment need."
Mechanism of Action and Clinical Evidence
Delandistrogene moxeparvovec-rokl is a recombinant gene therapy designed to deliver a gene that produces Elevidys micro-dystrophin, a shortened protein containing essential domains of the dystrophin protein found in normal muscle cells. The FDA's decision to expand approval was based on the debilitating nature of DMD and the significant unmet medical need. The original approval was granted through the accelerated approval pathway, reserved for drugs that are reasonably likely to provide clinical benefits for serious diseases.
The efficacy of Elevidys was evaluated in two double-blind studies and two open-label studies, encompassing a total of 218 male patients with confirmed disease-causing mutations in the DMD gene. One key study utilized the North Star Ambulatory Assessment (NSAA), a scale for rating motor function in ambulatory males with DMD. While the primary endpoint of improvement versus placebo on the NSAA was not met, the FDA considered secondary endpoints that indicated a clinical benefit, leading to the traditional approval.
For non-ambulatory individuals aged 4 and older, the FDA considered clinical data from studies in 4- to 7-year-old children, as well as a study in 4- to 5-year-old children, which demonstrated a correlation between Elevidys micro-dystrophin levels and positive clinical outcomes.
Challenges and Considerations
DMD primarily affects males, impacting approximately 1 in every 3,300 boys. The disease leads to progressive muscle weakness, resulting in life-threatening respiratory and heart problems. Symptoms typically manifest in childhood, and without intervention, patients often succumb to respiratory or heart failure in their 20s or 30s.
While the expanded approval of Elevidys represents a significant step forward, the cost of gene therapies remains a substantial obstacle. Individual costs for gene therapies can exceed $3 million per patient, potentially limiting access to this treatment. Analyses suggest that the annual cost of gene therapies could surpass $20 billion, posing a considerable financial burden on healthcare systems. It is crucial to ensure an adequate supply of gene therapies like Elevidys while addressing the financial challenges associated with these innovative treatments.
Alternative Approaches and Future Directions
Researchers at Indiana University School of Medicine have reported a novel gene therapy approach that restores full-length dystrophin protein, potentially offering advantages over micro-dystrophin therapies. Their triple-adeno-associated virus vector system has shown promise in improving muscle tissue and overall strength in mice models with DMD. This approach aims to deliver a complete version of the dystrophin protein, addressing limitations of truncated versions used in current gene therapies. Renzhi Han, PhD, a senior author of the study, believes this new approach offers significant advantages and is actively seeking further clinical development.
Sarepta's Perspective
Doug Ingram, president and chief executive officer of Sarepta, stated that the expanded approval "represent[s] many years of dedicated research, development, investment and creative energy" and that it "is a defining moment for the Duchenne community. Today also stands as a watershed occasion for the promise of gene therapy and a win for science."
