Regulators are poised to decide within days whether to clear a Cambridge biotech’s gene therapy for a deadly muscle-wasting disease that afflicts more than 10,000 boys and young men nationwide, even though questions remain about whether the treatment is safe and effective.
The prospect that the Food and Drug Administration could give “accelerated approval” to the single-dose treatment from Sarepta Therapeutics has buoyed families of boys with Duchenne muscular dystrophy. It has also drawn criticism from some scientists and health research experts who say the FDA is loosening its standards.
Jennifer Handt, a writer in Darien, Conn., whose 5-year-old son has Duchenne, said she has no doubt that Sarepta’s therapy works after watching a May 12 hearing of independent scientific advisers to the FDA. The panel narrowly recommended approval after it reviewed data and heard wrenching testimony from parents who want the gene therapy for their sons. The advisers also watched videos of boys in Sarepta’s clinical trial climbing stairs and playing baseball, after receiving the drug, demonstrating what their parents said was greater strength than prior to receiving treatment.
“That’s real world evidence,” said Handt, whose son, Charlie, was diagnosed with Duchenne at the age of 3 and is participating in a follow-up clinical trial by Sarepta to confirm that the gene therapy works. “This goes back to ‘believe your eyes.’” She added, “I’m not going to let this disease take my boy or take away the quality of life of my family.”
But the FDA, which plans to make its ruling by Monday, is grappling with skepticism from experts inside and outside the agency who say greenlighting the drug would be a misuse of the 31-year-old accelerated approval program. That process enables regulators to speed up approval for medicines targeting serious unmet medical needs if they show promise in clinical trials.
The program has hastened hundreds of drugs to market. But it drew fierce criticism in 2021 after the FDA cleared Biogen’s controversial Alzheimer’s drug Aduhelm, a costly medicine that some experts skewered as risky and ineffective. As in the case of Sarepta’s gene therapy, patients of families with Alzheimer’s disease had implored regulators to approve Aduhelm. But doctors and hospitals balked at prescribing the drug — and public and private insurers declined to cover it for most patients — making it a major commercial flop.
“Leadership at FDA is caught in a vise,” said Diana Zuckerman, president of the National Center for Health Research, a nonprofit that analyzes clinical studies, who contends that Sarepta failed to prove its gene therapy warrants accelerated approval. “There’s pressure to speed up drug approvals, and pressure to maintain scientific standards.”
Zuckerman told the FDA advisory panel earlier this month that Duchenne is a “terrible, terrible disease.” But she warned that the agency could damage its credibility if it granted a faster sign-off to an experimental therapy before it had clear evidence of its safety and effectiveness.
“If the FDA no longer represents the gold standard for approval, that poses risks for all Americans with serious diseases,” she testified.
Several biotechs in Massachusetts have won notable fast-track approvals in recent years for drugs that treat deadly degenerative diseases. They include a Biogen medicine called Qalsody in April for a rare form of ALS and an earlier controversial Duchenne treatment from Sarepta in 2016. Those approvals were based on limited clinical data and conditioned on “confirmatory,” or post-approval, data from follow-up trials.
Dr. Aaron Kesselheim, a prominent professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, said the FDA has shown greater flexibility for clearing medicines through the accelerated pathway — sometimes too much flexibility.
Two years ago, Kesselheim was among a trio of independent experts who quit another FDA advisory committee after the agency overruled the panel’s recommendation to reject Aduhelm, a drug approval he called “perhaps the worst” he has seen.
Faster approval “was intended for drugs with promise but that don’t maybe yet have totally clear evidence that they are effective,” Kesselheim said recently. “That doesn’t mean any drug can qualify.”
Patient advocacy groups have become more influential over the past decade, expanding their traditional role of supporting people with diseases. They draw public attention to life-threatening and rare disorders and raise money for research. In tacit alliance with biopharma companies, they also lobby the FDA to approve medicines, Congress to boost research spending, and Medicare to pay for drugs for older Americans.
“We don’t have the luxury of waiting for the perfect drug,” said Debra Miller, founder of the nonprofit CureDuchenne, which is pushing for accelerated approval of Sarepta’s gene therapy. “One approval will lead to further improvements and better treatments in the future.”
Sharp disagreements surfaced at the committee hearing about Sarepta’s clinical data, which some members and outside experts called ambiguous and inconclusive. The company’s drug would be the first gene therapy for Duchenne and is viewed as a model for other biotechs considering seeking accelerated approval for their own rare-disease treatments.
Sarepta chief executive Doug Ingram, in an interview, said the upcoming FDA ruling could be a “bellwether moment for genetic medicine and gene therapy itself,” providing guidance on how to bring “genetic science to therapies that actually help patients now.”
Duchenne is a genetic disorder marked by progressive muscle degeneration and weakness due to the alterations of a protein called dystrophin that helps keep muscle cells intact. It mostly affects boys, and symptoms usually begin between ages 2 and 3. By the time they turn 12, many can no longer walk. Until recently, boys with the disease did not survive much beyond their teens, but now some live into their 30s, according to the Muscular Dystrophy Association.
To combat the disease, Sarepta engineered a micro-dystrophin, which is a miniature version of the protein that is mutated in patients with the disease. In the clinical trial, that healthy protein was delivered through an infusion to slow Duchenne’s progression. The company described the levels of the shortened dystrophin protein in patients after infusions as a “biomarker” that could be used to predict clinical benefit over the longer term.
Ingram said his research team offered “brilliant evidence” to the FDA advisers that most patients will experience a “very significant” benefit from the treatment.
FDA staff reviewers, however, questioned how accurate the biomarker would be in assessing which boys might preserve muscle as a result of the gene therapy. They cited data showing that some boys who received Sarepta’s drug showed no greater improvement in muscle function than those given a placebo.
Accelerated approval of the therapy for boys who can still walk would enable Sarepta to proceed with tests in older boys and young men in wheelchairs, as well as in a smaller percentage of Duchenne patients with antibodies that cause them to reject the drug. Eventually, Ingram said, the treatment could help up to 95 percent of patients.
Some advisers who favored approval in the 8-to-6 vote said they were swayed by testimony from parents who shared videos of their boys playing sports. Dr. Anthony Amato, a Harvard professor of neurology who has treated Duchenne for decades, called the videos part of the “compelling evidence this was effective” for some patients.
Other advisers said the benefits don’t outweigh the risks, including the possibility of liver damage. The data “doesn’t rise to the threshold of substantial evidence,” said Caleb Alexander, a public health professor at Johns Hopkins.
An FDA approval could raise false hopes and close off other options for patients, according to some critics.
Boys who get the treatment “could forgo any future opportunity to get [another] gene therapy” if a better one emerges, cautioned Michael Abrams, a senior researcher at Public Citizen’s Health Research Group. That’s because the gene therapy dose is delivered to patients through a capsule of viruses known as a viral vector that could trigger an immune response against a subsequent therapy, he said.
But the advisory panel’s patient representative, Christopher “Buddy” Cassidy, a Virginia man with Duchenne, said patients who are rapidly losing muscle function are willing to take that chance.
One prominent biotech executive said the FDA shouldn’t let the perfect be the enemy of good, echoing patient advocates who believe drugs offering only modest improvement can be a bridge to better ones.
“The first treatment is never the best” in any class of drugs, said Stoke Therapeutics CEO Ed Kaye, who preceded Ingram as Sarepta’s chief executive and shepherded an earlier and similarly contentious Duchenne drug, Exondys 51, to approval in 2016. Sales of that drug, he said, enabled Sarepta to pay for the research that led to the gene therapy.
Robert Weisman can be reached at firstname.lastname@example.org. Jonathan Saltzman can be reached at email@example.com.