FDA review begins for full approval bids on 2 Duchenne therapies

The U.S. Food and Drug Administration (FDA) is expected to decide by Feb. 28, 2027, whether to grant traditional approval to Amondys 45 (casimersen) and Vyondys 53 (golodirsen), two exon-skipping therapies designed to treat certain people with Duchenne muscular dystrophy (DMD).

Both medications are currently approved in the U.S. under the FDA’s accelerated approval pathway, which allows a therapy to be made available based on early clinical data suggesting it will likely benefit patients. As a requirement of this approval, drug developers have to run additional testing aimed at verifying clinical benefit, with long-term approval contingent on the results.

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Applications seek traditional approval

Now, Sarepta Therapeutics — which markets both Amondys 45 and Vyondys 53 — has submitted applications asking the FDA to convert the therapies from accelerated approval to traditional approval. The FDA has agreed to review the applications and has set a target action date of Feb. 28, 2027.

“The FDA’s acceptance of these applications for review is an important step for the Duchenne community,” Louise Rodino‑Klapac, PhD, president of research and development and technical operations at Sarepta, said in a company press release.

DMD is a genetic disorder caused by mutations in the gene that encodes dystrophin, a protein that’s vital for muscle health. People with DMD produce little to no functional dystrophin protein, leading to progressive muscle damage that drives disease symptoms.

The gene encoding dystrophin contains many segments, called exons. When the gene is read to produce protein, the exons are strung together to form a full protein-coding sequence, sort of like putting together many words to form a sentence. Many DMD-causing mutations disrupt the gene’s reading frame, resulting in a scrambled set of instructions that produces no functional protein.

The basic idea behind exon-skipping therapies for DMD is to skip over certain exons so the rest of the instructions are back in frame, allowing cells to produce a shortened but functional version of the dystrophin protein that may help preserve muscle health. The FDA’s decisions to grant accelerated approval to Amondys 45 and Vyondys 53 were based on early clinical trial data indicating that these therapies increased dystrophin production in skeletal muscle in patients with amenable mutations.

ESSENCE trial helps support FDA review

Sarepta’s applications seeking conversion to traditional approval are based in large part on a Phase 3 clinical trial called ESSENCE (NCT02500381). The study enrolled boys with DMD, ages 6 to 13, with mutations amenable to exon 45 or exon 53 skipping. Participants were randomly assigned to receive the appropriate exon-skipping therapy or a placebo for about two years.

The ESSENCE trial was designed to show that treatment with exon-skipping therapies would lead to better outcomes in a test of motor function that measures how quickly patients can walk up four stairs. Sarepta announced late last year that the trial had missed its goal — although stair-climbing times were on average a bit faster with the therapies than the placebo, the difference was not statistically significant, meaning it could have been due to chance.

When it announced the results, Sarepta said the trial results were likely skewed by disruptions due to the COVID-19 pandemic, which affected roughly a quarter of participants. Analyses excluding those participants showed an average difference of 0.11 steps per second favoring the exon-skipping therapies over the placebo. This difference was also not statistically significant, but Sarepta has said the magnitude of difference is clinically meaningful. The company also highlighted that safety data from ESSENCE were in line with the therapies’ known profiles, with almost all side effects being mild or moderate.

In addition to data from ESSENCE, Sarepta’s applications also include published real-world evidence on patients treated with Amondys 45 or Vyondys 53 in real-world clinical practice.

Real-world evidence also supports review

“The submissions draw on the ESSENCE study and years of published real-world evidence, which together offer a fuller understanding of how these therapies benefit patients and change the progression of disease,” Rodino‑Klapac said. “Within Duchenne, each amenable mutation defines an ultra-rare population—a small subset of an already rare disease. Across our exon skipping therapies, more than 1,800 people worldwide have been treated, and we continue to observe preservation of muscle function and slowed disease progression. In populations this small and in a disease where damage unfolds over years, real-world experience is essential to understanding how these therapies impact the disease course.”

Pat Furlong, president and founder of the advocacy group Parent Project Muscular Dystrophy, said the FDA’s decision to review Sarepta’s applications “reflects both the progress the Duchenne community has made over the past several years and the needs that remain, while maintaining a commitment to evaluating therapies with rigor.”

“We appreciate the FDA’s continued willingness to apply regulatory adaptability in addressing the unique challenges of rare disease drug development. … We are grateful for the FDA’s engagement with the Duchenne community and the Agency’s dedication to advancing therapeutic options through pathways adaptable to rare disease,” Furlong said.