FDA delays decision on Duchenne gene therapy, considers narrower approval
24 May 2023
Phase 3Gene Therapy
The Food and Drug Administration has delayed its review of a closely watched gene therapy for Duchenne muscular dystrophy by one month, taking more time to consider whether approval should be initially limited to children who are most likely to benefit.
In a statement Wednesday, the treatment’s developer, Sarepta Therapeutics, said the regulator needs “modest additional time” to complete its review and will now decide whether to grant an accelerated approval by June 22. The delay will involve final negotiations around the information that would be included in the drug’s label, as well as the post-marketing commitments it will require of Sarepta. The FDA had previously set a May 29 deadline for its decision.
Sarepta said the regulator is working towards “potentially” clearing the treatment for use in Duchenne patients between 4 and 5 years of age. An ongoing, placebo-controlled Phase 3 study would serve as a confirmatory trial and, if positive, could support a broader, non-age restricted label, Sarepta added. Results from that trial are expected by the end of the year.
A Sarepta spokesperson declined to comment further. Shares of the company fell by 8% at market open Wednesday.
Sarepta is seeking FDA clearance based on its treatment's ability to help people with the disease make a diminutive protein, called microdystrophin, that’s thought to protect muscle. Additionally, there were signs in testing that some participants did better than medical history suggests they should have.
However, in the only placebo-controlled test of Sarepta's gene therapy so far, treatment didn't meaningfully improve patients' function. Further analysis by the company after the fact suggested that participants who were 4 to 5 years old did better than those who were older.
The mixed data presents a challenge for the FDA, which has appeared divided over whether to clear the treatment. At a meeting of FDA advisers 12 days ago, agency scientists questioned the significance of microdystrophin and were generally skeptical of Sarepta's results. Their views were shared by some of panelists, who ultimately voted 8-6 to recommend the FDA grant Sarepta an accelerated approval.
The results in younger children were the “most compelling” evidence, Raymond Roos, a professor of neurological science at the University of Chicago Medical Center, said at the meeting. “Perhaps the difference in the lack of improvement in the 6- to 7-year olds is because they started at a different level.”
The ongoing confirmatory study could soon answer some of the doubts held by FDA staff and agency advisers. But the short timeline also raises risks for the FDA, which could approve the therapy only to see that trial produce negative data.
Celia Witten, the acting director of the FDA office that reviewed Sarepta’s therapy, said at the meeting that the FDA would “expect to remove” the therapy from market if the study fails.
Duchenne is a progressive, muscle-wasting condition that almost exclusively affects boys. Because their muscles get weaker with time, it’s likely that the earlier a gene therapy is administered, the better, Jerry Mendell, the director of Nationwide Children’s Hospital’s gene therapy research and a Sarepta study investigator, said in a recent interview.
“It makes sense, because you’re treating robust muscle that is more likely to be receptive to receiving the gene,” he said. Scar tissue also builds up as patients age, making it harder for muscles to contract and for the therapy to have an impact. “Even if you get transduction and gene expression, those [muscle] fibers are not going to work as well,” Mendell said.
Still, the potential limits for Sarepta’s treatment, at least initially, are “a bit surprising,” wrote Brian Abrahams, an RBC Capital Markets analyst who covers Sarepta, in a note to clients. “While this had always been viewed as a possible middle-ground to more cleanly justify an expedited approval given the better data in these patients, it had not been formally discussed at length during the [FDA meeting],” Abrahams wrote.
Editor’s note: This story has been updated with additional detail, quotes and analyst commentary.
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