Clinical studies to date "do not provide unambiguous evidence" for SRP-9001 (delandistrogene moxeparvovec), an investigational gene therapy for ambulatory Duchenne muscular dystrophy patients, FDA reviewers said in released ahead of an advisory committee meeting.
The agency also raised safety concerns about the possibility of administering an ineffective gene therapy.
Duchenne muscular dystrophy is characterized by a mutation that leads to a lack of dystrophin and muscle loss. It affects about one in 3,300 boys and has no known cure.
SRP-9001 is designed to deliver a gene that codes for a shortened form of dystrophin, called micro-dystrophin, to help preserve muscle. To qualify for accelerated approval, Sarepta Therapeutics proposed expression of micro-dystrophin -- a novel, engineered protein -- as a surrogate endpoint.
On Friday, the FDA's Cellular, Tissue, and Gene Therapies Advisory Committee will meet to discuss whether micro-dystrophin levels 12 weeks after SRP-9001 treatment can serve as a surrogate endpoint that the gene therapy is reasonably likely to predict clinical benefit.
Corticosteroids are the primary pharmacologic treatment for Duchenne. In addition, four exon-skipping drugs -- including three from Sarepta -- have received accelerated FDA approval for patients with specific DMD mutations; their clinical benefit has not yet been verified.
The goal of SRP-9001 treatment is to change the disease trajectory of Duchenne muscular dystrophy into a milder, Becker muscular dystrophy (BMD)-like phenotype, FDA staff said. But no epidemiologic or pathophysiologic evidence of micro-dystrophin's function is available, the agency pointed out.
"The protein differs in important ways from both the endogenous shortened forms of dystrophin in patients with BMD, and the internally truncated dystrophins expressed through exon-skipping drugs," the agency reviewers wrote.
"Measurement of levels of Sarepta's micro-dystrophin in muscle tissue only provides information about expression of the transgene product in cells transduced by SRP-9001, rather than insight into a pharmacologic effect on a biomarker in the pathway of the disease," they added.
The briefing report assessed nonclinical data and three clinical studies, including a randomized, placebo-controlled trial. That study failed to demonstrate a statistically significant effect of treatment with SRP-9001, but exploratory subgroup analyses suggested a possible benefit for ambulatory patients, ages 4 to 5 years.
Still, the FDA reviewers said it was challenging "to conclude with reasonable certainty from the data provided by the Applicant either that SRP-9001 is likely effective for younger patients, or that it is likely ineffective for older patients or those with somewhat poorer functional status."
In addition, accelerated approval of an ineffective gene therapy poses a unique risk, the agency noted. Due to the immune response associated with adeno-associated virus (AAV) vector-based treatment, patients who receive SRP-9001 would be unable to receive a second dose if needed, or subsequent treatment with another AAV vector-based gene therapy in the future.
The FDA documents showed a long history of regulatory interactions about SRP-9001, with the agency saying it was not convinced micro-dystrophin was a good endpoint for accelerated approval as far back as 2018. The report also revealed a clinical hold on an SRP-9001 trial in 2021 following an adverse event of asthenia in a 9-year-old patient requiring hospitalization and respiratory support.
SRP-9001 currently is being studied in the randomized, double-blind, placebo-controlled trial of 125 Duchenne patients ages 4 to 7. Sarepta has proposed EMBARK as the post-marketing confirmatory trial for SRP-9001. Other companies also are developing AAV gene therapies for Duchenne.
On Friday, the FDA advisory committee will discuss the clinical implications of Sarepta's finding to date, as well as the potential risks, benefits, and uncertainties of accelerated approval of SRP-9001.
The FDA plans to decide whether to approve SRP-9001 by May 29. The agency is not required to follow its advisory committee's advice, but it often does.