May 10, 2023 08:51 Updated: FDA report raises concerns over Sarepta Duchenne gene therapy ahead of accelerated approval decision Lei Lei
Ahead of what’s certain to be a closely watched advisory committee meeting Friday, the FDA outlined concerns on the efficacy and safety of Sarepta Therapeutics’ gene therapy for Duchenne muscular dystrophy.
In briefing documents released Wednesday, the FDA said there was a lack of “unambiguous evidence” that Sarepta’s gene therapy, known as SRP-9001, is likely beneficial for patients with Duchenne. The FDA raised myriad concerns over whether clinical trial results translated into benefit for patients, alongside safety and manufacturing issues related to the viral vectors used to deliver the treatment.
On Friday, a panel of outside experts will convene in a day-long meeting to discuss and vote on whether or not they believe Sarepta’s gene therapy should be granted accelerated approval based on currently available data.
Sarepta’s gene therapy encodes for a miniaturized version of dystrophin, the protein that is mutated in patients with Duchenne muscular dystrophy. The therapy is not meant to be a cure, but rather is meant to slow the progression of the disease, where boys usually die in early adulthood.
An accelerated approval would be based on whether expression of that micro-dystrophin reasonably predicts clinical benefit, but the FDA raised a number of questions around the use of micro-dystrophin as a biomarker for approval. The miniaturized version of dystrophin is missing a tail that is found in normal dystrophin and which contributes to muscle function, the FDA wrote, so the agency is not convinced that the engineered version of the protein can provide clinical benefit.
Pooled data from Sarepta’s randomized and single-arm studies suggest that micro-dystrophin expression 12 weeks after the therapy is administered is associated with change in performance on a motor function test for Duchenne patients after one year.
“However, the persuasiveness of such associations is uncertain,” the FDA wrote, noting that two-thirds of patients in the analysis were from open-label studies as opposed to blinded and randomized studies, meaning that data could be biased to favor improvement on the motor function test.
Additionally, the FDA noted that the lack of association in micro-dystrophin levels and performance of the test in patients ages 6 and up further put into question whether micro-dystrophin could be used as a biomarker for approval. Sarepta filed for accelerated approval after the drug failed a randomized trial. The biotech pointed to exploratory analyses that suggested the gene therapy had an effect on patients between the ages of 4 and 5, but there was no difference in outcomes in patients between 6 and 7 years of age.
Because of the mixed study results, the FDA noted there was uncertainty around what age group should get the gene therapy.
The FDA also outlined several safety concerns. Primary among those were worries around the viral vectors, known as AAVs, that are used to deliver the gene therapy. AAV therapies can cause liver toxicities and immune reactions in patients. In addition, the FDA noted that the commercial manufacturing Sarepta is using results in a greater percentage of empty AAV capsids, which can trigger safety events with less potential benefit from the therapy. Previously, the therapy was being manufactured at Nationwide Children’s Hospital, but the commercial product will be manufactured by Catalent.
Notably, the briefing documents revealed an undisclosed clinical hold on the trial in 2021, after a 9-year-old patient was hospitalized and needed respiratory support following a case of asthenia. Public companies are required to report material events, but Sarepta did not disclose the safety event or clinical hold in 2021.
Lastly, on safety, the FDA cautioned that administration of this gene therapy could prevent patients from getting future AAV gene therapies that prove to be effective. Other companies, including Pfizer and Regenxbio, are developing AAV gene therapies for Duchenne.
The agency had initially not planned to hold an advisory committee for Sarepta’s gene therapy, but reversed its decision later on. And while the FDA generally follows the recommendations of its advisory committee, it is not required to do so. The FDA has until May 29 to decide whether or not to grant the gene therapy accelerated approval.
If the treatment were to win accelerated approval, Sarepta is required to complete a confirmatory study on the gene therapy. Results from that randomized trial are expected in September. Sarepta previously won accelerated approval for three exon-skipping therapies for Duchenne patients with specific mutations, but has yet to complete the confirmatory trials for those drugs.
Sarepta declined to comment on the briefing documents.
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