"If it were to receive an accelerated approval, it would need to have a confirmatory data from a clinical trial to support continued approval," remarked Peter Marks, director of the FDA's Center for Biologics Evaluation and Research. Earlier in the week, FDA staff scientists had outlined a number of concerns about the application, ultimately concluding that clinical studies of SRP-9001 did "not provide unambiguous evidence" of benefit in ambulatory patients with DMD, and that it also posed a risk of patients not being able to receive other more effective AAV vector-based gene therapies in the future. The agency's presentation on Friday continued in the same vein, casting doubt on the structure of Sarepta's microdystrophin, a shortened form of dystrophin encoded by the therapy, as well as on preclinical testing, clinical trial results and manufacturing. Panel member Nirali Shah, who voted against, said "I don't have any real concerns about the risk of therapy, I think it's well tolerated, but I do remain concerned about the actual benefit, and whether that has been adequately demonstrated without a study that is going to be using the commercialised product." She added that "coming from a field of gene therapy – the product is the process – and I think the confirmatory study needs to be completed." Meanwhile, Rajiv Ratan said he was not convinced that Sarepta's data package "provided plausibility that the expression the microdystrophin would predict clinical outcome."
Caleb Alexander, who also voted no, said he agreed that videos shown to the panel of boys who had been treated and appeared to achieve improved muscle function were "compelling and there are good clinicians here that think this product works…but as we heard, accelerated approval is based on more than that, and the threshold of substantial evidence has to be met."
The regulatory filing included results from a study, dubbed Study 102, which showed that while SRP-9001 succeeded on the main biological endpoint of micro-dystrophin protein expression, there was no significant difference between SRP-9001 and placebo on the functional endpoint assessing improvement on the North Star Ambulatory Assessment (NSAA) rating scale at 48 weeks. Sarepta is currently evaluating its gene therapy in the Phase III EMBARK trial, also known as Study 301, in about 125 DMD patients between the ages of 4 to 7 years old, and proposes that it could serve as the post-marketing confirmatory study. EMBARK is expected to read out by the end of 2023. Among those who voted yes were Donald Kohn, who said "giving accelerated approval will give patients access to this over the next year, while the results from the definitive study are being analysed….We need to err on the side of patients being given the benefit of access." John Chiorini, who voted yes, said "waiting is not going to be beneficial to the patients."
For a more in-depth take, see Spotlight On: Can this week's Duchene gene-therapy AdCom skirt controversy?