Sarepta plans to seek full FDA approval of 2 Duchenne treatments
Exon-skipping therapies Amondys 45, Vyondys 53 show promise, company says
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Sarepta Therapeutics plans to ask the U.S. Food and Drug Administration (FDA) to grant full approval for Amondys 45 (casimersen) and Vyondys 53 (golodirsen), two exon-skipping therapies designed to treat certain people with Duchenne muscular dystrophy (DMD).
The company said it met with the FDA to discuss plans for the two therapies, and the FDA signaled that the company will be allowed to include clinical trial data as well as real-world data in its application, which Sarepta expects to submit before the end of April.
“In rare diseases like Duchenne, where progression varies widely and meaningful functional changes unfold over years—not months—incorporating real-world data alongside clinical findings can help us better understand long-term outcomes,” Louise Rodino‑Klapac, PhD, president of research and development and technical operations at Sarepta, said in a company press release. “This is especially true for therapies targeting ultra-rare, genetically defined subgroups, where confirmatory studies are inherently complex.”
DMD is caused by mutations in the gene that encodes dystrophin, a protein that’s key for preserving muscle health. Within a cell’s DNA, this gene contains both exons (the parts providing information to make protein) and introns (non-coding elements that help control the gene’s activity). When the gene is read, the whole sequence is copied over into a template, then the introns are removed and the exons are strung together to form a protein-coding sequence.
Many DMD-causing mutations result in the exons falling out of alignment, and, as a consequence, a garbled sequence that doesn’t produce any functional dystrophin protein at all. Exon-skipping therapies aim to skip over certain exons to get the rest back into alignment, allowing production of a shortened but functional version of the protein. Amondys 45 aims to skip exon 45, while Vyondys 53 aims to skip exon 53.
Accelerated approval
Both therapies are approved in the U.S. under the FDA’s accelerated approval program. This is a type of conditional approval where the FDA allows a therapy to be marketed based on early clinical data that it will likely benefit patients. Amondys 45 and Vyondys 53 were approved based on early data showing they could increase dystrophin protein levels.
A condition of accelerated approval is that the drug’s developer needs to run additional testing to prove the therapy improves outcomes for patients. If results are positive, developers can apply for a transition to full traditional approval, as Sarepta now intends to do. Several exon-skipping therapies have been granted accelerated approval by the FDA, but so far none has transitioned into full approval.
Sarepta said its planned application will include real-world data that the company has collected since Amondys 45 and Vyondys 53 launched, as well as data from the Phase 3 trial ESSENCE (NCT02500381).
The ESSENCE trial tested Amondys 45 or Vyondys 53 against a placebo in boys with DMD who had amenable mutations. The study hoped to show that these exon-skipping treatments would improve outcomes on the four-step ascend velocity test, which measures how quickly a person can walk up four stairs. Sarepta announced a few months ago that the study had missed its main goal: Although patients given exon-skipping therapies tended to be faster, the difference wasn’t statistically significant, meaning it could plausibly be random chance.
Although ESSENCE failed to show a statistically significant effect, Sarepta has argued that the magnitude of improvement may be clinically meaningful, especially after accounting for disruptions to the study due to the COVID-19 pandemic. In a recent poster, the company also highlighted new analyses suggesting patients who were predicted to decline in the four-step velocity test tended to decline less if given exon-skipping therapies. Sarepta has also touted the overall positive safety profile of these therapies in clinical trials and real-world testing.
Although the FDA has said it will consider data from ESSENCE and real-world data for Sarepta’s application, whether the agency judges these data as sufficient to prove that Amondys 45 and Vyondys 53 is effective will be decided when the application is actually under review.
“We appreciate the FDA’s openness to our submitting the supplemental applications for AMONDYS 45 and VYONDYS 53 and willingness to consider all available data – from the ESSENCE confirmatory study and the real-world evidence generated over the past several years,” Rodino‑Klapac said.
