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Once in limbo, promising Duchenne muscular dystrophy drug back on track toward approval Once in limbo, promising Duchenne muscular dystrophy drug back on track toward approval
(about 1 hour later)
A new drug designed to slow the progression of Duchenne muscular dystrophy, a devastating disease that overwhelmingly affects boys and typically leaves them needing wheelchairs by their teens and dead in their 20s, has received a long-awaited boost from the Food and Drug Administration. For much of last fall and winter and into this spring, scientists at the Food and Drug Administration wavered over what to do about a potential new drug to slow the progression of­­ ­Duchenne muscular dystrophy, a devastating disease that overwhelmingly affects boys, leaving most in wheelchairs by their teens and dead in their 20s.
Massachusetts-based Sarepta Therapeutics said Monday that FDA officials detailed a potential path forward for the drug, eteplirsen, and indicated a willingness to consider it for accelerated approval. The news puts eteplirsen one step closer to becoming the first approved treatment for Duchenne, a disease that affects about one in 3,500 boys globally. In a clinical trial involving 12 boys, the drug appeared to have halted physical decline. That gave hope to parents desperate for a treatment, but regulators expressed skepticism about the reliability of the study’s results.
“This provides the opportunity to get the drug approved and in the hands of all the boys who can benefit from it sometime in 2015,” Sarepta chief executive Chris Garabedian said in an interview. “I think that’s a huge win for the [Duchenne] community and for Sarepta.” Convinced that this drug could succeed where others had failed, the families of patients mounted an aggressive campaign to pressure the FDA. They argued that it was up to the agency to decide whether their sons would be the last generation of boys to die from Duchenne, or the first to survive. They hired a public relations firm and bombarded Facebook and Twitter, posted online YouTube videos of boys benefiting from the drug, rounded up more than 100,000 signatures for an official White House petition, visited lawmakers on Capitol Hill and made their case to top FDA officials in a series of face-to-face meetings.
The move follows a tumultuous year in which the FDA initially appeared headed toward swift approval of eteplirsen based on promising results from a trial involving 12 young boys, whose muscular deterioration seemed virtually halted by the drug. But the agency hit the pause button in November, saying it would be “premature” for Sarepta to seek approval of its drug after the failure of a separate trial involving a different Duchenne treatment that used similar technology. On Monday, Massachusetts-based Sarepta Therapeutics disclosed that although the FDA reiterated its skepticism regarding data surrounding the drug, eteplirsen, the agency has detailed a potential path forward for the drug and indicated a willingness to consider it for accelerated approval. That news came five months after the FDA told Sarepta that it would be “premature” for the company to seek approval and suggested that Sarepta might first need to conduct a larger trial, which could mean years of delay.
Months of behind-the-scenes deliberations followed over the effectiveness of eteplirsen, as well as an aggressive public campaign waged by patients’ families determined to keep pressure on the agency. Families met with top FDA officials repeatedly, filed a White House petition in support of the drug’s approval, posted online videos of boys benefiting from eteplirsen and argued that the FDA was far too slow to act on evidence that the drug was stabilizing children who otherwise would decline rapidly. The company, whose stock soared by 40 percent Monday, said it plans to file a new drug application with the agency and will push forward with a larger “confirmatory” study that will allow more boys access to eteplirsen and give regulators more robust data about its safety and effectiveness.
“Kids on this drug are having remarkably different lives than they would have otherwise,” Mindy Leffler of Bellevue, Wash., said in a recent interview. She has been pushing for the drug’s approval in hopes of accessing it for her 10-year-old son, Aidan, who has begun to lose function in his legs. “When you’re talking about something that has zero side effects, with good potential to work, I don’t understand the need for caution moving forward. . . . Who the hell cares, if the kid is walking when he shouldn’t be?” “This provides the opportunity to get the drug approved and in the hands of all the boys who can benefit from it sometime in 2015,” Chris Garabedian, Sarepta’s chief executive, said in an interview. “I think that’s a huge win for the [Duchenne] community and for Sarepta.”
Duchenne is caused by a mutation in the gene responsible for producing dystrophin, an essential protein involved in muscle function. Without dystrophin, even routine activities can damage muscles, causing them to die and be replaced by fat and other tissue. It is typically diagnosed in boys by age 6. The steady progression of the disease leaves many boys immobile by the time they are teenagers, and eventually can affect the heart and respiratory muscles, making breathing difficult. Although the FDA action doesn’t guarantee approval, the development brought relief and joy to many Duchenne families and put eteplirsen a step closer to becoming the first treatment for the disease, which affects about 15,000 boys in the United States.
Eteplirsen uses an approach called exon skipping, intended to bypass the existing mutation and restore a gene’s ability to produce dystrophin. The goal is to create enough dystrophin production to transform Duchenne into a milder and more sustainable form of muscular dystrophy known as Becker. But difficult questions remain, and they go beyond any one drug:
In more than two years since Sarepta’s clinical trial began, the results have proved encouraging. Although many questions remain about how much dystrophin the drug actually helps to produce, the drug appears to have halted the decline for the boys in the trial, while showing no adverse side effects. How does the FDA balance its traditional role of ensuring that drugs that reach the market are both safe and effective with the obvious urgency to make treatments available to children facing a fatal disease? How much weight should the agency give to the voice of parents and patients, who often are willing to shoulder outsize risks? Should the FDA go ahead and approve promising drugs if it isn’t convinced that they will work over the long term, knowing they will cost patients and insurers hundreds of thousands of dollars a year?
“It’s unequivocal. Since the day the kids were started on eteplirsen, they basically have never changed again. The natural history of the disease is to decline,” said Jerry Mendell, a pediatric expert at Nationwide Children’s Hospital in Columbus, Ohio, and the lead investigator on the Sarepta trial. “I see it as a game changer.” “It’s a big dilemma,” said Louis Kunkel, a Harvard geneticist who is credited with discovering the gene behind Duchenne and who has aided in the search for a cure. “I’ve waffled on my opinion of this. If you listen to the families, they make a good argument why this should be available. . . . [But] how well it’s working is an academic argument that hasn’t been settled yet. And I think that’s where the hesitancy of the FDA is. . . . It’s an extremely hard thing.”
Only about 13 percent of Duchenne patients have mutations that could benefit from eteplirsen, but Sarepta is developing similar drugs to treat boys with other exon deletions, along with clinical trials to test them. For its part, the FDA seems to be walking a careful line with ete­plirsen. Regulators have made clear that they still harbor doubts even as they give Sarepta a chance to make its case without requiring a larger study before initial approval. On Monday, the agency said only that it recognizes “the devastating nature of the disease on patients and their families” and is working with patient groups and pharmaceutical companies to make effective Duchenne drugs available as soon as possible.
The company said Monday that even as the FDA said its evaluators “remain skeptical” about the persuasiveness of some of Sarepta’s data, the agency encouraged it to push forward later this year with a larger “confirmatory” study that would provide more robust data about eteplirsen’s safety and effectiveness. For many parents of children with Duchenne, the case seems clear-cut: Eteplirsen is producing results, they say. And though questions remain about exactly why it works, it’s better to go ahead and treat boys who are dying while scientists parse the particulars.
In the short term, that means as many as 100 additional patients — some older and some younger than the boys in the current trial — could gain access the drug prior to FDA approval. That study also is unlikely to have a placebo group, Garabedian said, meaning that every child enrolled will receive the drug. “Kids on this drug are having remarkably different lives than they would have otherwise,” said Mindy Leffler of Bellevue, Wash., who has been pushing for the drug’s approval in hopes of getting it for her 10-year-old son, Aidan, who has begun to lose function in his legs. “When you’re talking about something that has zero side effects, with good potential to work, I don’t understand the need for caution moving forward. . . . Who the hell cares, if the kid is walking when he shouldn’t be?”
“They know that the patients are waiting for this,” said Garabedian, who has said that the drug, if approved, could be among the most expensive ever in the United States. Duchenne is caused by a mutation in the gene responsible for producing dystrophin, an essential protein involved in muscle function. Without dystrophin, even routine activities can damage muscles, causing them to die and be replaced by fat and other tissue. Duchenne is typically diagnosed in boys by age 6. The disease’s steady progression leaves many boys immobile by the time they are teens. It eventually affects the heart and respiratory muscles, making breathing difficult.
Not everyone faults the FDA for taking so long to decide how to proceed on eteplirsen. Eric Hoffman, director of the Center for Genetic Medicine at Children’s National Medical Center and a longtime Duchenne researcher, said valid questions remain about eteplirsen’s dystrophin-producing abilities and how effective Sarepta’s drug really is over the long term. Eteplirsen uses an approach called exon skipping, intended to bypass the existing mutation and restore a gene’s ability to produce enough dystrophin to transform Duchenne into a milder and more sustainable form of muscular dystrophy known as Becker. Only about 13 percent of Duchenne patients have mutations that could benefit from eteplirsen, but Sarepta is developing similar drugs to treat boys with other exon deletions, along with clinical trials to test them.
“For accelerated approval, FDA wants a compelling case, and this is a case that’s been challenging to make compelling,” Hoffman said in an interview this month. “I’ve personally been very impressed with the FDA. They’ve been extremely interactive. . . . There’s every indication they are taking this extremely seriously.” In the more than two years since Sarepta’s clinical trial began, the drug appears to have substantially halted the decline for boys in the trial without causing harmful side effects. “It’s unequivocal,” said Jerry Mendell, a pediatric expert at Nationwide Children’s Hospital in Columbus, Ohio, and the lead investigator on the Sarepta trial. “I see it as a game-changer.”
Even Louis Kunkel, a Harvard geneticist credited with discovering the gene behind Duchenne, said recently that he is “of mixed mind” on whether Sarepta has proved that eteplirsen is ready for FDA approval. On one hand, he said, the results are incredibly promising. On the other, Duchenne patients have faced many disappointments with therapies that seemed to offer hope but ultimately failed. Not everyone faults the FDA for taking so long to decide how to proceed. Eric Hoffman, director of the Center for Genetic Medicine Research at Children’s National Medical Center and a longtime Duchenne researcher, said valid questions remain about eteplirsen’s dystrophin-producing abilities and how effective Sarepta’s drug really is.
“I’ve waffled on my opinion of this,” Kunkel said. “If you listen to the families, they make a good argument why this should be available. . . . [But] how well it’s working is an academic argument that hasn’t been settled yet. And I think that’s where the hesitancy of the FDA is.” “I’ve personally been very impressed with the FDA,” he said. “There’s every indication they are taking this extremely seriously.”
Earlier this month, asked about eteplirsen during an event in Boston, FDA Commissioner Margaret A. Hamburg underscored the agency’s efforts to seek input from patients and said the agency understands the urgency to find treatments for Duchenne, according to an account in the Boston Business Journal. But she defended the FDA’s deliberate process, saying, “We want to develop products that will really make a difference.” Hoffman said he understands the families’ sense of urgency, and he shares optimism about exon skipping. But he said the public campaign to pressure the FDA has divided the community more than united it.
Despite the recent tensions between federal regulators and families affected by Duchenne, the fact that eteplirsen now has a clear path toward approval is likely to bring a measure of hope and relief for people such as Jenn McNary of Massachusetts. “It becomes this form of bullying that puts everybody between a rock and hard place,” he said. “Unless you’re supporting kicking out the head of the FDA and granting accelerated approval as quickly as possible, then you’re supporting killing Duchenne kids.”
Her 12-year-old son, Max, has flourished during his two years in the eteplirsen trial. Without the drug, his mother said, he probably would be in a wheelchair. Instead, he is running and playing with friends and has recently tried riding a bike. Meanwhile, his 15-year-old brother, Austin, did not qualify for the Sarepta trial. He must use a wheelchair and recently began to lose the ability to feed himself. McNary believes that if Austin also can get access to the drug soon, it could halt his decline. He said that the reality is more nuanced and that FDA reviewers do want to help patients but are wary about setting a precedent by approving high-priced drugs they aren’t yet convinced will work.
“This is about stopping the progression of the disease; this was never a cure,” McNary said. “If we could just freeze it while we let smart people figure it out further, that would be fine with me. . . . That’s the one thing that none of us have is any time to waste.” Despite the tensions of the past year, Monday brought cautious optimism for parents such as Jenn McNary of Massachusetts. Her 12-year-old son, Max, has flourished during two years in the ete­plirsen trial. But his 15-year-old brother, Austin, did not qualify for the Sarepta trial. He must use a wheelchair and recently began to lose the ability to feed himself. McNary believes that if Austin can get access to the drug soon, it could halt his decline. She plans to continue to push the FDA to act quickly.
“This is about stopping the progression of the disease; this was never a cure,” McNary said. “If we could just freeze it while we let smart people figure it out further, that would be fine with me. . . . The one thing that none of us have is any time to waste.”