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The Food and Drug Administration approved the first gene therapy for Duchenne muscular dystrophy, but limited access to those ages four and five. In an eagerly anticipated decision, the Food and Drug Administration Thursday approved the first gene therapy for muscular dystrophy. "Today's approval addresses an urgent unmet medical need and is an important advancement in the treatment of Duchenne muscular dystrophy, a devastating condition with limited treatment options, that leads to a progressive deterioration of an individual's health over time," said Dr. Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, in a statement. But the agency rejected a request to make the treatment available to all children with Duchenne muscular dystrophy, the most common form of the incurable muscle disease, who could still walk. Instead, the agency restricted access to patients ages four and five until more evidence is available that the therapy is safe and effective. The decision elicited mixed reactions. Parents of children suffering from the genetic disorder, advocates and some doctors and researchers welcomed the limited approval. But some were disappointed the treatment isn't being made more widely available right away. "Today is a very important day," Debra Miller, who leads CureDuchenne, an advocacy group, told NPR in an interview. "But every single day these boys are losing muscle cells. And so when you have a son with Duchenne and you see them getting weaker right before your eyes, you know we have to get therapies to patients sooner rather than later."

FDA's accelerated approval came with limits

Others, however praised the agency's restraint, though some argued even the limited approval was premature. "This is a really critical decision for the FDA to get right," Dr. Caleb Alexander of Johns Hopkins University told NPR in an interview. Alexander voted against approval during a May meeting of an FDA advisory committee that narrowly recommended the agency grant approval. "This has implications not only for those who may receive this product. But it also sends an important signal regarding what the FDA will require for future products to treat this and similarly devastating diseases," Alexander said. The company that developed the treatment, Sarepta Therapeutics of Cambridge, Mass., said the therapy would be available as soon as possible. The treatment, called Elevidys, will cost $3.2 million for each patient, the company announced shortly after the approval. Sarepta asked the FDA to approve the gene therapy under a program that allows the agency to provide access to treatments before direct evidence is available that they are effective. But this accelerated approval process is controversial because some companies fail to follow through on their promises to confirm their treatments work. A drug approved this way to prevent premature birth was recently withdrawn after being found useless. Sarepta's muscular dystrophy treatment is the first gene therapy approved under the program. The disease, which almost exclusively affects boys, destroys muscles. Most boys end up in wheelchairs before they become teenagers. Eventually, their hearts and lungs give out. Most people with the disease die in their 30s or 40s. The gene therapy works by infusing trillions of harmless viruses in single treatment that has been genetically modified to ferry a gene to patients' muscles.

Evidence for the gene therapy is indirect

The gene produces a miniature version of a protein called dystrophin, that boys with muscular dystrophy are missing or don't have enough of. The hope is this "micro-dystrophin" will at least help slow the progression of the disease. But there's an intense debate about this. Sarepta based its request on how much micro-dystrophin it produces in patients' muscles — without direct evidence that's actually helping alleviate symptoms and prevent disease progression. During the May advisory meeting, parents and doctors showed dramatic videos of children who could barely stand and walk, running, biking and and easily climbing stairs after the treatment. But Alexander and other experts say it remains unclear the treatment is responsible and is safe. "This product is not without risks. And I think the evidence is murky," Alexander says. "The evidence really doesn't meet the bar required to reach market." And children who receive the treatment may then be ineligible to get other treatments in the pipeline that may be more effective. "That's a really non-trivial concern," Alexander said.

But others said there is sufficient evidence to warrant broader approval, including preliminary evidence the treatment is improving boys' muscles, as well as animal data and clear evidence the therapy boosts micro-dystrophin in muscles. "What's the old expression: 'Don't let perfect get in the way of good?' " said Jeffrey Chamberlain, who directs the Muscular Dystrophy Research Center at the University of Washington. That said, Chamberlain was glad the FDA at least approved the treatment for younger children pending further data. "You'd like to see approval for as broad a range of patients as possible. But we'll take what we can get at this point," Chamberlain said. Michael Kelly, the chief scientific officer for CureDuchenne, says he hopes this will lead to other, even more effective gene therapies for the disease. "This is a critical and really important step in treatment and this is going to lead the way and blaze a trail for the next round of better therapeutics," Kelly told NPR in an interview.

Advisers voted 8-6 in favor of an accelerated approval despite uncertainty around the treatment’s benefit. The agency is set to make a final decision by May 29. 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. 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.