Opinion: Sarepta Enters Uncharted Territory with Adcomm Approval

Pictured: Sarepta Sign on a brick building/Sarepta Therapeutics

On May 12, an FDA advisory committee recommended the regulator approve Sarepta Therapeutics’ gene therapy, SRP-9001, to treat Duchenne muscular dystrophy. While the FDA has yet to decide whether or not to approve SRP-9001 based on priority review, Sarepta successfully convinced 8 of 14 advisers that it could address multiple outstanding issues raised by the agency.

However, the discussion highlighted issues developers of future gene therapies need to consider.

As an investigational gene therapy, SRP-9001 delivers a gene that codes for a shortened, functional form of dystrophin to muscle cells. As the FDA demonstrated by holding the adcomm meeting, handling uncharted gene therapies—even from a DMD market leader—should involve cautious judgment. However, while asking for reproducible results from Sarepta may reinforce our understanding of whether SRP-9001 works safely and efficaciously, doing so may delay the delivery of much-needed advanced treatments to patients with an unmet need. If the FDA chooses to ask for more data to inform its perspective, it will have a potentially chilling effect on the future of accelerated approvals for gene therapies.

There were four specific issues raised during the adcomm. These centered around manufacturing and nonclinical issues, establishing adequate surrogate endpoints, safety concerns and confirmatory study results.

Manufacturing issues raised by the FDA involved a change in manufacturing processes between trials that may have confounded results. While the FDA has yet to prove directly that confounding occurred, any manufacturing process changes that alter the quality of the administered product may be scrutinized more closely by the FDA in the future. Companies developing future gene therapies may find their products under increased scrutiny if the data appears unclear due to potential confounders.

Regarding surrogate endpoints, North Star Ambulatory Assessment scores from Sarepta’s trials indicated that DMD patients aged 4 to 5 years benefitted more from SRP-9001 than older children, raising questions about how the data were stratified and whether the analysis adequately accounted for the heterogeneous nature of DMD progression. In addition, while trial participants were assessed for response to treatment for up to a year after dosing, longer-term efficacy endpoints have not been clinically established.

Concerning safety, SRP-9001 is a novel gene therapy agent, so side effects are not yet clearly defined. While Sarepta did not report any significant safety concerns, successful extensive monitoring is crucial to the company’s success going forward, as well as for other biotech companies developing gene therapies.

Part of this monitoring will come from the ongoing confirmatory study known as EMBARK, which follows patients for more than two years after dosing. Sarepta expects to have results by the end of 2023. But because DMD affects only approximately 10,000 patients in the U.S., this small patient population will present a persistent challenge for clinical trial recruitment and trial data analysis. For other companies tackling rare diseases with gene therapies, a higher bar for evidence could similarly pose challenges in terms of recruiting enough patients to provide evidence.

Regardless of the outcome of the overall priority review process for SRP-9001, change is inevitable in the gene therapy space. If the FDA approves SRP-9001 on or before May 29, Sarepta will have a smoother path to commercialization. However, a request for more information or a complete rejection will lead to further scrutiny for Sarepta and future gene therapies that come under FDA review. Whichever way it goes, the decision will affect the FDA’s processes as it continues to refine its approach to regulating gene therapies.

Jia Jie Chen writes analyses focusing on drug development in the biotech and pharma industries for BioSpace. He has a doctorate degree in pharmacy and experiences ranging from biotech equity research to business intelligence analysis. Follow him on LinkedIn.