Duchenne Muscular Dystrophy Treatment Narrowly Captures Support of FDA Advisors

FDA advisors narrowly supported accelerated approval for Sarepta Therapeutics’ investigational gene therapy for Duchenne muscular dystrophy (DMD) on Friday.

In a 8-to-6 vote, the agency’s Cellular, Tissue, and Gene Therapies Advisory Committee said the overall benefits and risks supported SRP-9001 (delandistrogene moxeparvovec) for ambulatory Duchenne patients, using expression of Sarepta’s micro-dystrophin as a surrogate endpoint. None of the 14 voting members abstained.

“I know there were pluses and minuses in the study,” said committee member Anthony Amato, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, who voted to support approval. “But I thought there was compelling evidence that there is an effect. Looking at videos and taking care of people with muscular dystrophy for over 30 years, you don’t get these benefits. It’s not a placebo response.”

Whether the close vote means the FDA is more likely to approve the drug than previously indicated remains to be seen. In pre-meeting briefing documents, the agency stated that clinical studies to date “do not provide unambiguous evidence” for SRP-9001 to treat Duchenne.

DMD 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. Corticosteroids are the primary pharmacologic treatment for Duchenne, and four exon-skipping drugs — including three from Sarepta — have received accelerated FDA approval for patients with specific DMD mutations. The clinical benefit of these exon-skipping drugs has not been verified in confirmatory trials.

SRP-9001 delivers a gene that codes for a shortened form of dystrophin — a novel, engineered protein called micro-dystrophin — to help preserve muscle. To qualify for accelerated approval, Sarepta proposed expression of micro-dystrophin as a surrogate endpoint.

The goal of SRP-9001 treatment is to change the disease trajectory of DMD into a milder, Becker muscular dystrophy (BMD)-like phenotype, but no epidemiologic or pathophysiologic evidence of micro-dystrophin’s function exists, the FDA noted. 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 added.

In addition, the FDA expressed concerns about possibly giving a gene therapy that doesn’t work. Patients have one shot with gene therapy due to the immune response the treatment generates, the agency explained, and could not receive any of the other gene therapies currently being developed.

Friday’s meeting was fueled by debates about the implications of Sarepta’s clinical data, including a placebo-controlled trial of SRP-9001 that failed to demonstrate a statistically significant treatment effect, though subgroup analysis suggested possible benefits for boys, ages 4-5 years. The company also showed videos of patients running, playing on a playground, and climbing stairs after they received the therapy.

“I think quality of life is very important here and we need to seriously take into account what we’re seeing in the videos,” said Christopher “Buddy” Cassidy, MA, of Annandale, Virginia, a patient representative on the committee who voted in favor of approval.

“I agree that the videos were compelling and there are good clinicians here who think this product works,” noted committee member Caleb Alexander, MD, MS, of Johns Hopkins University Bloomberg School of Public Health in Baltimore, who voted “no.”

But accelerated approval is more than that, Alexander emphasized. “The threshold of substantial evidence has to be met whether a product is being approved under the standard pathway or accelerated pathway,” he said.

The FDA’s decision could affect the entire field of Duchenne drug development, Alexander pointed out. “There’s a reason why our regulatory framework is regarded as the gold standard around the world and it’s because of the careful science and careful work the FDA and sponsors do, working together to bring new products to market,” he said. “The totality of evidence we’ve reviewed today, and that we reviewed in the briefing, simply doesn’t rise to the threshold of substantial evidence that’s required for accelerated approval.”

Some committee members also voiced concerns about confirmatory trials if SRP-9001 is granted accelerated approval. “We are very serious that, if this were to receive an accelerated approval, it would need to have confirmatory data from a clinical trial to support continued approval,” said Peter Marks, MD, PhD, director of the FDA Center for Biologics Evaluation and Research. “The agency understands the importance of getting these post-approval commitments — in this case, the confirmatory trial — answered.”

SRP-9001 currently is being studied in the placebo-controlled EMBARK trial, which Sarepta has proposed as its post-marketing confirmatory trial.

The FDA is scheduled to decide whether to approve SRP-9001 by May 29. The agency is not required to follow its advisory committees’ recommendations, but often it does.