‘The luckiest of the unlucky’: A Duchenne gene therapy brings hope to families — and tests the FDA
The diagnosis was news no parent ever wants to receive. Susan and Chris Finazzo heard it twice in two months.
Both of their children, Chase and Dylan, have a genetic disease called Duchenne muscular dystrophy. The progressive condition slowly and unstoppably lays waste to muscles, first stealing away the ability to walk, then weakening the lungs and heart.
The hopes they held for their children’s future were darkened by fears of a shortened life, and dread of when Chase and Dylan would no longer be able to climb a playground slide, dress independently or swallow food.
“You’re just sitting there like, this is not what was supposed to happen,” Susan said. “You’re mourning the death of the life that you thought your child was going to have.”
The Finazzos didn’t accept the outlook doctors gave their sons, though. They trawled through the internet looking for answers to their many questions. They met with patient advocates to learn about experimental medicines being developed, and enrolled Chase and Dylan in a clinical trial of a cutting-edge gene therapy.
“We always say we’re the luckiest of the unlucky,” she said. “This gives us hope.”
The Finazzos are part of a large network of parents and patient advocates who believe the gene therapy, developed by biotechnology company Sarepta Therapeutics, represents a medical breakthrough for Duchenne. The treatment is an infusion meant to change the course of the disease for years, if not permanently. Available medicines, by comparison, are thought to only slow Duchenne’s relentless advance, not halt it, as a gene therapy might.
“There isn’t a parent, family or person with this diagnosis that doesn't go to bed every night and say, ‘Stop the disease right here. Let it be stopped,’” said Pat Furlong, president and CEO of Parent Project Muscular Dystrophy, a prominent patient advocacy group. “The community believes this is a very important step forward.”
Sarepta has asked the Food and Drug Administration for an “accelerated” approval, a type of clearance that’s used to speed treatments for serious diseases like Duchenne to market. The company’s case is supported by data showing its drug produces large amounts of a potentially helpful protein, as well as signs some study participants are doing better than medical history suggests they should.
“I am not, as I sit here today, aware of an approved therapy under the accelerated approval pathway with more compelling evidence than we have,” said Sarepta CEO Doug Ingram.
Yet the treatment failed an important part of its only placebo-controlled test to date. The effects of the protein it helps produce, a diminutive molecule called microdystrophin, aren’t fully understood. Nor is how long any benefit might last. An approval, if granted, would set a precedent for other gene therapy developers to follow, raising the stakes of the agency’s decision.
The FDA is expected to issue its verdict by late June, months before a Phase 3 study will deliver results that either confirm or refute the benefit of a treatment likely to cost more than $1 million. In May, the regulator convened a group of outside experts to discuss it — a meeting reportedly scheduled because of intra-agency disagreement about the strength of Sarepta’s application. The experts narrowly recommended the FDA grant an OK.
“This is a very, ‘between a rock and a hard place’ situation for the FDA,” said Dae Gon Ha, an analyst at the investment bank Stifel, who covers gene therapy companies.
Seventeen years ago, Tim Revell’s son Timothy was having trouble walking.
A whirlwind of brain and blood tests followed, confirming that Duchenne was why Timothy, then 2, had fallen behind his peers. The Revells’ doctor told Tim that all he could do was go home and love his son.
Timothy is one of an estimated 300,000 people worldwide, almost exclusively boys, who have the condition, which is caused by a genetic mutation that stops the body from making a muscle-protecting protein called dystrophin. A few years later, the Revells learned Timothy’s younger brother had it too.
Parents of children with Duchenne have long received the same advice as Revell heard in 2006. “There’s zero hope,” he recalls being told.
Revell became an advocate for drug research and got his sons into earlier clinical trials of Duchenne medicines that ultimately proved unhelpful. In the meantime, he's watched the disease slowly take hold. Timothy lost the ability to walk three years ago.
“Duchenne is like death by 1,000 cuts,” he said. After years of decline, death often occurs in young adulthood, when the muscles of the heart or lungs fail.
There are a few treatments available. Some patients with particular mutations can get drugs known as “exon-skippers,” which help the body produce a shortened form of dystrophin that’s thought — but not proven — to modestly slow progression. Others, like Revell’s sons, aren’t eligible.
However, most rely on steroids, which can slow muscle damage but cause other problems like weight gain, weak bones and behavioral changes.
“It's not a great choice, and it's not an easy one for parents to make,” said Jennifer Handt, whose 5-year-old son Charlie has Duchenne. “The expectation is to hopefully buy a little bit of time until science can give us something more tangible.”
For decades, patient advocates have put their hopes in gene therapy, a way of shuttling replacements for missing or damaged genes into the body to restore needed proteins like dystrophin. Until recently, it had always seemed just out of reach.
“I remember in my first meeting 30 years ago, it was raised, ‘At some point we'll have gene therapy,’” said PPMD’s Furlong, “and it sounded way back then like, ‘Oh my gosh, what will it take to get there?’”
‘A significant adversary’
Jerry Mendell saw his first Duchenne patient in 1969, during a postdoctoral fellowship at the National Institutes of Health.
“We didn't know anything about the disease” then, he said. “Just what it looked like under a microscope.”
What started as a fellowship became a lifelong mission for Mendell, who in the following decades emerged as a top researcher in the field of neuromuscular disease.
In 1989, he and his team at Ohio State University published research that established the steroid prednisone as the standard of care for Duchenne. In the late 1990s, he was the first to test a gene therapy for another neuromuscular condition in humans and later conducted an early gene therapy experiment in Duchenne. More than a decade later, after Mendell became director of gene therapy research at Nationwide Children’s Hospital, the team he assembled invented Zolgensma, a dramatically beneficial medicine for infants born with the rare condition spinal muscular atrophy.
“I understood the potential for gene therapy if we could make it work” for Duchenne, he said. “There were many scientists and clinicians who doubted it, but to me it was the best approach we had.”
Duchenne presents several vexing scientific problems, however.
The disease has been seen as a target for gene therapy since the 1980s, when its genetic roots were first identified. But the gene that encodes for dystrophin is too large to be packaged into the microscopic viruses researchers use to deliver corrective gene therapy. And because Duchenne affects muscle, researchers need to use very high doses to shuttle in enough genetic material to hope for a benefit.
“This disease is a significant adversary,” said John Brandsema, a pediatric neurologist at the Children’s Hospital of Philadelphia. “We have been hammering away at it for decades.”
Scientists have spent years searching for workarounds, “dissecting” the gene and trying to figure out how to make it small enough to fit into the virus, Mendell said.
The solution was found in people with a milder form of the condition known as Becker muscular dystrophy. Patients with Becker have a large deletion in the middle of their dystrophin gene, but are still able to make a shorter version of the protein, explained Timothy Lotze, a pediatric neurology professor and director of a muscular dystrophy care center at Texas Children's Hospital. Published research has described a Becker patient who, while missing nearly half of that gene, was still walking at 61 years old.
Those insights sparked a rush among rival research groups to develop gene therapies built around “micro” or “mini” forms of the dystrophin gene, many of which were later licensed to or acquired by biopharmaceutical companies.
One program from the laboratory of Jude Samulski at the University of North Carolina was picked up by Pfizer. Another, from Jeff Chamberlain at the University of Washington and Dongsheng Duan at the University of Missouri, ended up in the hands of a biotech called Solid Biosciences.
Nationwide’s work, co-invented by Mendell and one of his recruits, Louise Rodino-Klapac, was acquired by Sarepta. It was a decision made by former CEO Ed Kaye, who had unsuccessfully tried to license Zolgensma years earlier.
“I knew Jerry would be first in the clinic and get it done quickly,” he said in a 2019 interview with Xconomy. “In this business, it’s who gets there first that’s important.”
Jennifer Handt wrestled with whether to enroll her son Charlie in one of Sarepta’s trials.
She met with other parents, visited different trial sites and “did her homework,” including vetting the doctor who would treat Charlie.
Still, it wasn’t a decision she made lightly.
“I had that moment of, ‘Is this the right thing to do?’” Handt said.
Early study results from Sarepta had shown the company’s gene therapy could produce levels of miniature dystrophin markedly higher than previously reported in trials of other Duchenne medicines — well beyond the amount that researchers think will alter the disease.
Yet data have been more mixed as to whether those protein levels translate to functional benefits. In some cases, boys who would have been expected to decline on tests evaluating their ability to walk, stand and balance, haven’t yet, which some experts point to as evidence the treatment is working.
“What we're seeing is stabilization of the disease that we've never been able to stabilize before,” said CHOP’s Brandsema, who is an investigator in multiple Duchenne gene therapy trials, including Sarepta’s. “That is a tremendous achievement.”
While Handt couldn’t be sure Sarepta’s treatment would help, Charlie’s disease was certain to progress. “What is our alternative?” she said. “The idea of doing nothing, when we had something, was not an option.”
Still, the gene therapies being developed for Duchenne, including Sarepta’s, use trillions of copies of the viral shells that deliver dystrophin DNA into the body. Though the virus in question has been safely used in scores of gene therapy experiments, prominent researchers have warned higher doses administered intravenously might not be as benign.
Those alarms have some merit. Four children died in a study of a gene therapy for a different type of neuromuscular disease. And while most of the side effects so far associated with Duchenne gene therapy appear manageable with close monitoring and a short course of immune-suppressing drugs, some rare but serious events have caused concern.
One patient died in a trial of Pfizer’s Duchenne gene therapy in 2021. Solid’s research was stalled multiple times due to safety worries. Data to date suggests Sarepta’s gene therapy to be generally safe, but it, too, was linked to one case of serious muscle weakness that researchers believe to be a shared effect among microdystrophin gene therapies. The company has excluded patients with certain mutations from testing in response.
“We have to be very aware that this is an irreversible decision when we do this. It's like transplanting an organ or doing surgery,” said Brandsema. “We cannot take it back once we’ve given it, and the reaction can be significant.”
Echoes of eteplirsen
Seven years ago, hundreds of patients and family members traveled to a Washington, D.C., suburb to testify in support of an emerging treatment for Duchenne.
The drug, known then as eteplirsen and also developed by Sarepta, was up for an accelerated approval. The FDA had gathered a panel of experts to review the evidence.
The data primarily came from a clinical trial of just 12 boys with Duchenne, and reviewers were skeptical. The treatment produced a tiny amount of dystrophin — less than 1% of normal levels — and it was very difficult to discern whether it had an effect.
However, parents, patients and doctors were convinced the drug worked. At the meeting, some chided FDA officials, drawing cheers from the audience. Although the panel ruled narrowly against eteplirsen that day, the agency’s top drug evaluator, Janet Woodcock, overruled her own review team, concluding the dystrophin levels were “reasonably likely” to result in a benefit. Her decision was supported by Robert Califf, the FDA commissioner then and now.
Eteplirsen’s approval caused a rift within the agency. Multiple reviewers left afterwards. In emails made public following the decision, Woodcock was accused by other staff members of flouting agency norms, keeping unusually close ties with Sarepta and patient advocates, and deciding to approve before reviewers had completed their evaluation.
Outside of the FDA, the approval was viewed as an example of the growing pressure patient groups — many of which receive some degree of funding from drug companies — were putting on regulators.
“That advisory committee meeting harmed relationships within the [Duchenne] community, with the FDA, and the perception of our community outside,” PPMD’s Furlong said.
Sarepta still hasn’t completed a required trial to confirm whether eteplirsen, which is now sold as Exondys 51, actually changes the disease’s course.
According to Ingram, the company’s CEO, the post-marketing study requested by the FDA won’t directly answer that question, only whether higher doses might be more beneficial. He pointed instead to real-world evidence presented at a recent medical meeting, as well as a study showing dystrophin levels as low as 0.5% of normal are associated with milder disease. Neither type of data is as conclusive as results from a placebo-controlled trial.
In the meantime, Sarepta has become one of biotech’s most valuable companies, currently worth about $12 billion. It followed a similar blueprint as Exondys 51 to bring two more drugs to market for different subsets of Duchenne patients, and began investing in gene therapy.
“In my view, we wouldn’t have [the gene therapy] today” without Exondys 51’s approval, he said. “It’s clear the FDA did the right thing.”
A new controversy?
In March, Peter Marks, head of an FDA office that reviews new drugs, stood before more than 1,000 researchers, patient advocates and doctors to give a speech on gene therapy.
Marks spoke of the agency’s urgency to speed development of gene therapies for rare and life-threatening diseases, and the tools the FDA had to help. Among those was the accelerated approval pathway, which has been criticized in the years following Exondys’ clearance and only used once before for a gene therapy.
Marks acknowledged the criticism. Some see speedy approvals as “a shortcut,” he said. But “we can’t be so careful about our approvals under accelerated approval that we prevent potentially life-saving therapies from getting to market in a timely manner,” he added.
The comments were notable given the venue. Marks was speaking at the yearly meeting of the Muscular Dystrophy Association, a large nonprofit group that supports research into neuromuscular diseases like Duchenne.
The talk was days after the FDA had scheduled an advisory meeting to review Sarepta’s accelerated approval application — a meeting, Stat News subsequently reported, that Marks called after agency staff appeared ready to reject the treatment. Sarepta had previously said a meeting wasn’t expected.
The conflicting news jarred the patient community, as advisory committees add an element of risk to the review process.
“It made people step back a little bit,” said Debra Miller, head of the advocacy group CureDuchenne, adding that there’s “a real feeling” people need to band together to show the FDA “we're behind this.”
“We all feel there's a really good chance that the therapy is going to be approved,” Miller said.
Still, the tension highlights the risk Sarepta took by seeking an accelerated approval in the first place.
Weighing Sarepta’s case
The decision to file early, rather than wait for the results of the company’s ongoing Phase 3 trial, was made “after a lot of contemplation” within the company, according to Ingram.
One factor was time. If Sarepta waited, at least one more year would pass before the gene therapy could possibly become available. “In the life of a Duchenne kid, that’s a monumentally long time,” he said.
Ingram also pointed to the “totality of the evidence” Sarepta has already compiled. The treatment’s design is based on decades of research on the dystrophin genes of Becker patients, he said. It has been tested in about 150 boys and is supported by biological data suggesting it’s working. Children in the studies are doing better than normally would be expected and the therapy’s benefit may “grow with time,” he added.
Other experts interviewed by BioPharma Dive were supportive of the data as well.
“This looks like a highly beneficial drug with relative risks that can be managed,” said Lotze, of Texas Children’s, who isn’t involved in Sarepta's trials. “I would hope, and somewhat expect, that a treatment like this might halt further progression of disease or markedly slow it.”
Still, Sarepta’s closest competitor, Pfizer, chose to wait for results from a Phase 3 study before deciding whether to file an application for its gene therapy.
The reason, according to its development head of rare neurologic diseases, Dan Levy, is that it’s challenging to tease apart a drug’s effect by comparing the performance of Duchenne patients to historical data.
The patients who join a clinical trial and the ones involved in the “natural history” studies that document disease trajectory could be different. There are also biases and confounding factors that can skew results of the primary test used to measure Duchenne’s progression.
“We believe the good data is going to come from a placebo-controlled, randomized clinical trial,” Levy said. “We’ve received general guidance from regulators around that.”
There are other issues regulators and panelists wrestled with. Clearing Sarepta’s treatment would signal the FDA’s comfort with medicines that use “truncated,” rather than full-sized, genes, said Stifel analyst Ha. Yet the gene Sarepta’s treatment delivers isn’t identical to a gene of a Becker patient, raising questions about its impact. The company also hasn’t clearly shown a correlation between microdystrophin expression and patients’ performance in the clinical trials.
More glaringly, the treatment didn’t improve physical function in its only placebo-controlled test, an outcome Sarepta blamed on bad luck during the process for randomizing patients between drug and placebo groups.
The timing of Sarepta’s Phase 3 trial results adds another wrinkle. Sarepta designed the study with various adjustments meant to boost its odds of success. The risk of a study failure months after an approval could give regulators pause, however.
One former senior FDA official, who was granted anonymity to discuss the agency’s forthcoming decision, speculated the regulator might ask panelists to vote on whether a decision should be delayed until Sarepta releases data.
“The fact that they have a trial reading out relatively soon after the [decision] date is a big problem,” the official said. An approval would “let the genie out of the bottle. You’re not going to be able to put it back in if that trial is negative.”
Ingram is confident the trial will succeed. Still, he said Sarepta would carefully weigh the data if it fails. “We would of course do the right thing for patients,” he said, when asked by BioPharma Dive whether the company would withdraw the treatment in the event of a negative result.
‘Not the end game’
Christine Miller was cautiously optimistic when she enrolled her 7-year-old son George, who has Duchenne, in one of Sarepta’s trials. (At her request, BioPharma Dive changed her and her son's name to protect their privacy.)
School had become difficult for George. He couldn’t keep up with other kids during soccer, and lagged behind on the playground. Miller sensed George was frustrated with his body.
Miller turned to a gene therapy trial for help. She didn’t expect George to suddenly “walk an extra mile,” or be cured. She hoped he might be able to walk, play and visit the beach for a little longer. More time as a healthy kid before a better drug comes along.
“Time is the one thing you don't have with Duchenne,” she said. Like other parents of children involved in Sarepta’s trials, Miller was hesitant to discuss how her son has responded to treatment, fearful of jeopardizing the study. He’s “in line with the data Sarepta has published,” she said. “That’s meaningful.”
Patient advocates are similarly wary of overstating what gene therapy might do, or how widely it’ll be available if approved. The results so far have been less predictable than people anticipated, said CureDuchenne’s Debra Miller. Some patients may not be eligible because of safety reasons, age, or the state of their disease. Others will be ruled out because their bodies’ immune system may react to the virus that delivers Sarepta’s treatment.
Advocates don’t expect the therapy’s effects to last forever, either. They’re already pointing to newer technologies that might overcome gene therapy’s limitations, or ways people might get a second dose if the effects of the first wane.
“A few years ago, there was a great expectation that this was going to be a ‘one-and-done’ [therapy],” Miller said. “We’ve been sobered. We know this is not the end game.”
Doctors are also trying to manage families’ expectations. After speaking with the heads of various neuromuscular clinics, Lotze, of Texas Children’s, said many large centers will treat only one or two patients per month so they can closely watch those who receive treatment.
Brandsema, too, is girding for conversations in which he’ll have to tell desperate parents to wait months before their child can get access; that a treatment isn’t just one infusion, but a lifetime of monitoring afterwards.
“Beyond everything else, we have to make sure that we keep everybody safe,” Lotze said.
Mendell acknowledges the questions facing the treatment he helped invent. “That’s what science is: show me, prove it,” he said.
Yet Mendell takes a longer view. For decades, he’s diagnosed boys with Duchenne and watched them slowly waste away. In 1999, he “dreamed that someday we would be where we are today,” he said.
Now, Mendell talks of the boys he believes he’s helping and of the hugs he gets after a child shaken by a life-threatening diagnosis feels “new stature” after treatment.
“There is no better feeling,” he said.