A group of Food and Drug Administration advisers narrowly supported approving what could be the first gene therapy for Duchenne muscular dystrophy in a meeting Friday, clearing the way for the agency to make a closely watched decision later this month.
By an 8-6 vote, the panel recommended that the treatment, developed by biotechnology company Sarepta Therapeutics, be granted an “accelerated” approval. The close vote reflected a daylong back-and-forth over the treatment, and whether the protein it’s designed to produce in the body — called microdystrophin — is reasonably likely to benefit people with Duchenne who can still walk.
“I know there were pluses and minuses in the study,” said Anthony Amato, a committee member and chief of the neuromuscular division at Brigham & Women’s Hospital. “But again, I thought there was compelling evidence that there is an effect.”
“Taking care of people with muscular dystrophy for over 30 years, you don't get these benefits. It’s not a placebo response,” added Amato, who voted yes.
Others weren’t convinced, agreeing with the long list of data shortcomings outlined by FDA staff at the meeting.
“While the risks are low, there was no evidence of benefit and without some data showing benefit we're basically asking families to shut off any future short- or mid-term possibilities for treatment,” said Lisa Lee, a panelist and associate vice president for research and innovation at Virginia Tech. Lee voted no.
As Sarepta’s treatment is a gene therapy, delivered via engineered viruses, both committee members and FDA staff expressed concern that patients would not be able to receive another treatment like it, should Sarepta’s later prove ineffective. Treatment also comes with other rare risks like liver injury, although side effects were manageable in testing.
Christopher “Buddy” Cassidy, the committee’s patient representative, emphasized several times throughout the day that those risks are ones Duchenne patients are willing to take, grounding the at times dense scientific discussion with clear explanations of what the disease means to people who have it.
“Even just stabilization across three, four years, I can't tell you how meaningful that is, as a patient,” said Cassidy. “What I wouldn't give for another four years to just maintain the level of strength I have now.”
The FDA usually follows the advice of its advisory committees, but isn’t required to do so. The agency is set to make its decision by May 29.
While far from unanimous, the panel’s recommendation could make that decision easier, and marks an important moment for a Duchenne patient community that has long advocated for gene therapy.
“You've heard about the science and the data behind this treatment and its participants, but look at the video,” said Melanie Hennick, showing a video of her 12-year-old son Connor who enrolled in Sarepta’s study when he was 7. “Watch him jump and run and play … this gene therapy was our hope. Otherwise, the natural course of this disease would have been a reality.”
Duchenne is inherited, and over time causes the body’s muscle tissue to waste away. It is caused by a malfunction to the gene encoding for the muscle-protecting protein dystrophin, and affects an estimated 300,000 people worldwide, almost exclusively boys. People with Duchenne typically lose the ability to walk by adolescence and die in their 30s because of lung- or heart-related complications.
A few treatments, known as “exon skippers,” are currently available for some patients, and are thought, but not proven, to moderately slow the disease. Three of these drugs are sold by Sarepta. Most patients rely on steroids, which delay progression but also cause growth defects, behavioral changes and other problems.
Sarepta’s gene therapy is the most advanced of several similar, experimental genetic medicines. It works by delivering genetic instructions for microdystrophin protein, which is believed to protect muscle. The protein was designed by researchers to resemble a gene found in people with Becker muscular dystrophy, a milder form of the disease. Testing has shown Sarepta’s therapy can produce a large amount of it, underpinning expectations that the treatment could offer substantial benefits.
Experts previously interviewed by BioPharma Dive are optimistic the treatment could halt, or significantly slow the disease for years. They are convinced by the levels of microdystrophin expression observed in testing, as well as some evidence patients are doing better than medical history suggests they should.
The therapy has provided hope to patients, parents and patient advocates, many of whom have waited on gene therapy for years and view it as the best chance to delay the disease’s advance. “It’s all about buying time,” said Susan Finazzo, whose two sons have Duchenne and are both enrolled in a Sarepta trial. “The more time you have the better,” she told BioPharma Dive in a recent interview.
But FDA staff have been skeptical of Sarepta’s data. Reporting by Stat News indicated agency scientists were poised to reject the therapy earlier this year before Peter Marks, the head of the agency’s gene therapy office, intervened and scheduled Friday’s hearing.
“A management decision was made that this [review] would benefit from public discussion,” Marks said in response to a panelist’s question Friday.
Documents released ahead of the meeting revealed agency staff still hold significant doubts. Reviewers don’t believe the company has provided “unambiguous evidence” that its treatment works, and noted that the microdystrophin it produces is different from what’s found in Becker patients or from exon-skipping drugs.
“We believe that differences [between the types of dystrophin] are important and do contribute to the overall uncertainty of the plausibility of the Sarepta microdystrophin as a surrogate marker reasonably likely to predict clinical benefit,” said Emmanuel Adu-Gyamfi, one of the FDA’s reviewers, at the meeting Friday.
More glaringly, Sarepta’s therapy failed to improve patients’ function versus a placebo after one year in its only placebo-controlled trial to date, missing one of the study’s main goals.
“I don’t think we have statistical evidence that the drug works, although my guess is that some patients do get better,” said Steven Pavlakis, a committee member and a professor of neurology at SUNY Health Sciences University, who voted yes, on Friday.
Caleb Alexander, another panelist who’s been a skeptical voice on past FDA approval decisions and voted no, agreed that the placebo-controlled test is the treatment’s best gauge, despite the other data gathered by Sarepta. “The real money is in [that study],” he said Friday.
Other panelists were hesitant to support a clearance ahead of results from an ongoing Phase 3 trial that could confirm the treatment’s benefit. Initial data are expected in December, putting the FDA in a potentially difficult position should it approve the therapy only for the trial to fail.
Pressed early by panelists on this topic, Celia Witten, the acting director of the FDA office reviewing Sarepta’s therapy, indicated the agency would take a close look at the trial data when it’s available.
“The goal would be, if a trial fails, we would look at it and see what our interpretation would be, but we'd expect to remove it from the market,” Witten said.
Peter Marks, Witten's boss at the FDA, later returned to that point, emphasizing to the committee that the agency will need confirmatory data from Sarepta to support the drug's continued approval, should it be granted.
Jonathan Gardner and Christopher Newman contributed reporting.
Editor’s note: This story has been updated throughout with additional detail from the meeting.