The US Food and Drug Administration (FDA) Cellular, Tissue, and Gene Therapies Advisory Committee voted 8-6 in favor of accelerated approval for Sarepta’s gene therapy SRP-9001 (delandistrogene moxeparvovec) to treat patients with Duchenne muscular dystrophy (DMD) who are still able to walk. 

Most members of the panel thought the overall benefit and risk considerations supported the accelerated approval of SRP-9001 using the expression of Sarepta’s micro-dystrophin at Week 12 following the administration of the experimental treatment as a surrogate endpoint, even when the existing uncertainties were taken into account. 

Of the 8 members who voted “yes,” most said their decision was driven by the ability to give patients access to this new therapy as quickly as possible. Those voting in favor of the accelerated approval also said they thought the risk-to-benefit ratio of the potential new treatment seemed favorable. 

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“Time is muscle,” was a motto that was repeated many times during the discussion. “Waiting is not going to be beneficial to these patients,” said John Chiorini, PhD, one of the members who voted in favor of the accelerated approval. Christopher “Buddy” Cassidy, the patient representative and a patient with DMD himself, said he found the data presented by Sarepta “quite convincing.”

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The main concern of those members who cast a negative vote was doubts about the actual benefits of the therapy, and the inability of patients who are treated with SRP-9001 to receive another adeno-associated virus (AAV)-based therapy that may be proven to be more beneficial. 

“I really hate the idea of people going with something that may or may not be effective, and then not having a chance for something else,” said Susan Ellenberg, a statistician specializing in the design of clinical trials and in the safety of medical products who felt there were too many uncertainties with the data available at this point. 

The FDA will now consider the committee’s vote but has no obligation to abide by its recommendation. If approved, SRP-9001 will be the first-ever gene therapy indicated for the treatment of DMD.

“We will now take this back and do something that we have to do every day at FDA,” said Peter Marks, MD, PhD, director of the agency’s Center for Biologics Evaluation and Research (CBER) in his closing remarks “We have to manage through the uncertainty here and we will work with the sponsor . . . in the coming weeks”.

Committee Members Raise Several Concerns About SRP-9001

Sarepta made the case for its biologics license application (BLA) to the committee in the first half of the daylong meeting, following a review of the FDA’s regulations on accelerated approval.

“This day marks an important opportunity to continue to advance the treatment landscape in DMD,” said Craig M. McDonald, MD, director of the neuromuscular disease clinic at the University of California, Davis Children’s Hospital, and study chair in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study. 

The committee meeting was called because FDA reviewers said clinical studies “do not provide unambiguous evidence” that SRP-9001 is likely to be beneficial for patients with DMD who are still able to walk.

Four topics of concern were discussed and addressed by Sarepta during the morning portion of the meeting: (1) whether the expression of micro-dystrophin is reasonably likely to predict clinical benefit to qualify SRP-9001 for accelerated approval, (2) the results obtained in the phase 2, so-called Study 102 in terms of the effect of the treatment on the North Star Ambulatory Assessment (NSAA), a 17-item rating scale used to measure functional motor abilities in patients with DMD who are still able to walk, (3) the overall safety of the AAV gene therapy, and (4) the potential impact of an early approval on the completion of an ongoing confirmatory study for SRP-9001.

Jerry Mendel MD, professor of neurology and pediatrics at Nationwide Children’s Hospital and The Ohio State University College of Medicine in Columbus, who has dedicated his career to neuromuscular conditions including DMD, gave a background of the disease and the unmet medical need it represents. He said the NSAA is a well-established, validated, and reliable measure of global function. 

Sarepta representatives then gave a comprehensive overview of the gene therapy, explained why the expression of micro-dystrophin is valid as a surrogate endpoint, and argued that SRP-9001 met the criteria for accelerated approval. 

The results of the 3 clinical trials that tested the safety and efficacy of SRP-9001 were also discussed, as was the question of why external controls are valid. A summary of safety data from the studies and clinical perspectives based on trial data was also covered.

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Study results have shown that SRP-9001 is well-tolerated and has a favorable safety profile, said Eddie Darton, MD, executive medical director, safety evaluation and risk management at Sarepta, adding that no deaths occurred during the study. He also gave an overview of the proposed risk mitigations against possible adverse events that may arise as a result of the treatment. 

The committee’s 15 members comprised experts in the field of neuroscience as well as patient and industry representatives. 

DMD is a devastating neuromuscular condition caused by a mutation in the DMD gene, which encodes dystrophin, an essential protein for the health of muscle tissue. Because the gene is located on the X chromosome, the disease mostly affects boys, who lose the ability to walk, usually by age 12. The progressive nature of the disease means patients’ conditions deteriorate until they die in early to mid-adulthood.