FDA's Fast-Tracked Approval of Sarepta DMD Gene Therapy Criticized

The FDA’s decision to authorize therapies that do not meet their efficacy endpoints has cast a shadow over its accelerated approval process, as highlighted by David Rind, chief medical officer of the Institute for Clinical and Economic Review. Rind's critique, published in the Journal of the American Medical Association, focuses on Sarepta Therapeutics’ gene therapy Elevidys (delandistrogene moxeparvovec-rokl), which received the FDA’s accelerated approval in June 2023 despite not meeting its main efficacy goals in clinical trials.

Elevidys is designed to treat Duchenne muscular dystrophy (DMD), a rare and severe neuromuscular disorder caused by mutations in the dystrophin gene. These mutations lead to the production of a faulty protein, resulting in developmental delays and muscle weakness. The therapy works by introducing a functional copy of the dystrophin gene into patients' muscles. The FDA based its approval on the observed expression levels of the protein micro-dystrophin, which the agency deemed “reasonably likely to predict clinical benefit” for children aged 4 to 5, the demographic for which Elevidys is intended.

Despite this rationale, the decision was met with surprise and skepticism, particularly because Elevidys failed to show significant improvement in patients' functional performance compared to a placebo in its Phase I trials. Even internal FDA reviewers expressed doubts about the reliability of micro-dystrophin levels as a predictive marker for clinical benefit. These concerns were detailed in the briefing documents prepared for an advisory committee meeting, which noted that micro-dystrophin levels only indicate the expression of the transgene product in cells, without providing clear evidence of a pharmacologic effect on a disease-related biomarker.

The approval process was contentious, narrowly passing an advisory committee vote with support from eight of the 14 panelists. To maintain the availability of Elevidys, Sarepta conducted the confirmatory Phase III EMBARK study to evaluate the gene therapy’s clinical benefits. In October 2023, Sarepta announced that EMBARK had not met its primary endpoint, failing to show significant improvements in functional mobility compared to a placebo. Nonetheless, Sarepta described the findings as “robust evidence” of meaningful clinical benefit.

Earlier this year, the FDA accepted Sarepta’s supplemental Biologics License Application for Elevidys, with a decision expected by June 21, 2024. Rind also criticized the high cost of Elevidys, which is priced at $3.1 million per dose, making it one of the most expensive treatments globally. He underscored the issue by pointing out that the therapy has yet to demonstrate efficacy in two randomized trials and is not a curative solution.

This situation has brought to light significant issues regarding the FDA’s accelerated approval pathway, particularly the balance between urgent medical needs and the rigorous validation of clinical benefits. The discourse around Elevidys exemplifies the broader debate on how regulatory bodies should navigate the approval of high-cost therapies that show promise in preliminary markers but fail to meet primary clinical endpoints.