(CNN) — Most parents would not be thrilled with the idea of their children being hooked up to an IV bag full of trillions of viruses.
But for Melanie Hennick, whose son Connor has Duchenne muscular dystrophy, it was a chance she hoped would change his life.
“We knew this wasn’t a cure,” Hennick said. “But it was an opportunity.”
Melanie G Hennick
Connor Hennick was enrolled in the gene therapy study at the age of 7.
Connor is one of only dozens of children to have received SRP-9001, an experimental gene therapy aimed at slowing or stopping the progression of Duchenne muscular dystrophy (DMD). Current treatments for the disease, which tends to affect boys because of the way it is inherited, include steroids and, later, heart medication. But nobody stops it.
SRP-9001 uses viruses to deliver a copy of a gene into the muscles to balance the copy of a gene that causes the disease. Hennick and many other parents like her pleaded for expedited approval of the treatment at a meeting of outside advisers to the US Food and Drug Administration on Friday.
Advisors voted 8-6 to approve the treatment, and the FDA will now decide whether to follow their advice.
“The decision that the FDA must make does not only affect the patients in Study 301 [an ongoing confirmatory trial that Sarepta is running]; it affects the whole area of drug development for Duchenne,” said Dr. Caleb Alexander, a professor of epidemiology and medicine at Johns Hopkins University’s Bloomberg School of Public Health, who voted against recommending approval. “The body of evidence … simply does not meet the threshold required for expedited approval.”
dr Raymond Roos, a neurology professor at the University of Chicago Medical Center, voted in favour. “The downside of gene therapy here is relatively small compared to whether it actually helps the patient, and that’s why I voted yes,” he said.
dr Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said his agency will take the recommendation and “do something that we at the FDA have to do every day.” …We have to deal with the uncertainty here.”
The FDA’s decision, expected later this month, will not only impact families like Connor’s, but also how the agency regulates treatments like this more broadly: it would be the first of its kind, the only drug Treatments provide a gene to try to cure a disease – to get expedited approval, a quicker route through the regulatory process. Its approval would set a precedent for other drugs like this, which are based on so-called surrogate endpoints, a measure of what the drug does in the body before more clinical evidence is available.
“Approval of gene therapy for Duchenne muscular dystrophy will be tremendous,” said Jeffrey Chamberlain, a professor at the University of Washington School of Medicine who pioneered gene therapy approaches for the disease. “I think this will spur further research and advancement of gene therapies for other diseases.”
DMD patients don’t have much time to wait. Children with Duchenne typically lose the ability to walk before they reach their teens, and often don’t live well past their 30s, Chamberlain said. He is not directly involved with SRP-9001, which is being developed by Sarepta Therapeutics, and serves on the Scientific Advisory Board of another company working on DMD gene therapies, Solid Biosciences.
“Gene therapy seems like a really good approach to treating this disease because it’s a genetic disease,” Chamberlain said. “The cause of the disease is a mutation in a single gene.”
This gene is responsible for the production of dystrophin, a key protein in muscle cell structure.
“It’s a bit like the two-by-four walls that make up your house,” Chamberlain said. “It’s really important to just hold everything together.”
SRP-9001, invented at Nationwide Children’s Hospital in Columbus, Ohio before being licensed for development by Sarepta, delivers a miniaturized version of the dystrophin gene to cells and is designed to help them make a version of the muscle-maintaining protein.
In one important clinical study, the therapy appeared to do just that. However, another key goal was not met: a benefit in measuring muscle function, making it difficult for SRP-9001 to get through the FDA.
Sarepta blamed the result on an imbalance in the allocation of patients to the placebo and treatment groups. But key FDA reviewers don’t seem convinced.
“The clinical studies conducted to date do not provide conclusive evidence that SRP-9001 is likely to be of benefit to outpatients with DMD,” reviewers from the agency wrote in briefing documents released ahead of Friday’s meeting, citing Patients who are still able to walk – the group who will They are initially entitled to the treatment if it is approved.
Family after family who attended Sarepta’s trials, like the Hennicks, disagree with the investigators. They say they believe the treatment has helped their children walk and run in ways they could never have done without it.
“It really is a miracle,” said Nate Plasman, whose son Andrew, aged 4, received SRP-9001 as part of the January 2019 study.
Nate Plasman
Sara (left), Andrew and Nate Plasman on the day he was dosed in the January 2019 trial.
Andrew was away from school for more than two months when he got the experimental therapy, Plasman said, and when he came back, “his preschool teachers were blown away,” he recalled. “They ask themselves, ‘Who is this kid?’ He runs. he jumps He rides the tricycle. He’s up and down off the floor”—all things he wasn’t very good at before therapy.
Marit Sivertson, mother of 9-year-old Brecken, agrees.
“We’ve seen the incredible changes in our son,” she said. “He doesn’t just walk around. He runs; he swims; he dives He truly lives the life that every 9-year-old boy should live.”
Marit Sivertson
dr Jerry Mendell of Nationwide Children’s Hospital in Ohio, who developed the gene therapy, went with Brecken Kinney.
Sivertson and Plasman also spoke at Friday’s meeting. Her goal is not to secure therapy for her own children; Because it is designed as a one-time treatment, they would not take it again. They say they are committed to the children who are still waiting.
This wait is particularly painful for Daniel and Lindsey Flessner, who have two sons with DMD. Her 5-year-old son Mason is enrolled in the SRP-9001 clinical study. Her two-year-old Dawson is too young.
“Every trip, every fall, every time he gets up by climbing up his legs using his hands for stabilization, it always hurts on us,” Flessner said. “It’s very painful when parents watch their children fight because they know the only thing they can do is wait, even though they don’t have time to wait.”
Daniel Flessner
Lindsey and Daniel Flessner’s sons, Mason and Dawson, both have DMD.
In addition to questioning how well the treatment works, FDA reviewers raised concerns about safety, particularly “related to the possibility of ineffective gene therapy being administered.”
The reviewers focused on the opportunity cost: Because of the viruses used to deliver the gene, patients may develop an immune response that could render future doses ineffective.
Chamberlain said work is being done to find ways to give more doses if needed, but for now it is a one-off treatment.
In his opinion, this approach is currently the best hope for DMD patients.
“It’s not perfect,” he admitted. “It’s not a complete cure, but based on the clinical results published by Sarepta and a few other companies, I believe micro-dystrophin gene therapy works better than any other drug that’s been tested against Duchenne muscular dystrophy.”
It’s unclear how long the effects will last; Sarepta is still conducting trials and a confirmatory study would be required as part of an accelerated approval. Sarepta has proposed a trial, which the company is already running, to meet this requirement. The results are expected later this year.
For families living with DMD, there is also an opportunity cost of waiting. In its briefing documents for the FDA meeting, Sarepta estimated that accelerated approval would speed up widespread access to SRP-9001 by at least a year, a time when about 400 boys could lose their ability to walk and another 400 whose disease became more severe is advanced, would die.
Melanie Hennick said Connor was admitted to the trial just weeks before he was 8 years old. She said she believes therapy is the reason Connor is doing so well.
“We had the opportunity to see Connor grow up at 8, 9, 10, 11 and 12 with more abilities than we ever dreamed of,” she said. “He climbs stairs without help; he runs around; he plays football; he plays hockey; He plays on a baseball team. … Those are things we never thought we’d see, especially at 12.”