Sarepta sees path to full FDA approval for muscle disease drug despite Phase 3 trial failure
Two of Sarepta Therapeutics' drugs to treat different genetic subtypes of Duchenne muscular dystrophy in patients failed to pass the confirmatory studies required for accelerated approval from the FDA. Sarepta executives said there is still a path to traditional FDA approval, but that may rely on the regulatory flexibility the agency demonstrates to the company and other developers of rare disease therapies.
Sarepta's Vyondys 53, approved in 2019, and Amondys 45, approved in 2021, both quickly won regulatory approval after clinical trial results showed the treatment led to increased levels of dystrophin, a key muscle protein that Duchenne patients are deficient in. But these antisense oligonucleotide drugs still need to be tested in a longer, larger confirmatory study designed to assess a range of measures of muscle function in patients.
After the close on Monday, Sarepta reported preliminary Phase 3 results showing that the Duchenne drug treatment achieved numerical, but not statistically significant, improvement in the primary objective of measuring the time it takes patients to climb four steps. Sarepta said the negative results from the nine-year study were due to the Covid-19 pandemic, during which 43% of affected participants missed consecutive weekly doses of the drug. On average, study participants missed eight doses in a row.
Sarepta said the results, excluding data from 57 participants whose double-blind dosing periods overlapped with the pandemic, showed a 30% reduction in disease progression over two years compared with placebo, as measured by a four-step test. Speaking on a conference call Monday night, Sarepta CEO Doug Ingram acknowledged that excluding 57 study participants affected by the coronavirus would reduce the study's power. But he said that for the remaining 168 patients, the change was clinically meaningful. Ingram added that it's important to take a long-term view of Duchenne.
“One of the benefits of long-term commercialization of these therapies is that we can see what happens over the long term,” Ingram said. “You look at [Vyondys] Over six years, these children were actually delayed by almost three years in being in a wheelchair, and the timing of ventilation was significantly different. “
Drugs that fail confirmatory studies may have their marketing authorization revoked. Based on Sarepta's previous discussions with the FDA, Ingram does not believe this will happen with Vyondys and Amondys. The agency said the criteria for withdrawing marketing authorization would be “only if there is no relevant analysis to demonstrate clinical benefit,” Ingram said. He added that clinical trials and real-world evidence continue to support patient benefit. The company plans to discuss changing the Duchenne drug's status to traditional regulatory approval with the FDA.
Sarepta did not disclose results on the trial's secondary endpoint. But Louise Rodino-Klapac, the company's president of R&D and technical operations, said the goals, which include additional measurements of muscle function and biological endpoints, will be presented at future medical meetings.
Sarepta has had a rough year. Three patients who received Sarepta gene therapy died in 2025. Two of the patients received Sarepta's Elevidys, a Duchenne gene therapy that controversially switched its accelerated approval to a conventional treatment last year despite its confirmatory clinical trial failure. All three deaths were attributed to acute liver failure. Elevidys is still suitable for Duchenne patients who can still walk, but not for patients whose disease has progressed to the point where they are unable to walk. Discussions are ongoing with the FDA about changing the Elevidys immunosuppressive regimen to reduce the risk of liver injury.
Sarepta's third quarter 2025 financial report showed that revenue was US$399.4 million, a decrease of 14.5% from the same period last year. The company attributed the revenue decline to lower shipments of Elevidys. That puts more pressure on Sarepta to generate revenue from its long-standing Duchenne therapy, but financial analysts don't share the company's optimism about the drugs. William Blair analyst Sami Corwin said in a note to investors on Tuesday that the Phase 3 study's failure to achieve its primary objective was a negative development.
“While management is confident that Vyondys 53 and Amondys 45 will not lose marketing authorization as a result, we are more skeptical and believe the stock's reaction (down 37% after hours) suggests investors are concerned about the future of these two products as well,” Corwin wrote.
Photo: Dina Mariani, Getty Images
