This article originally appeared in Genome in July 2017.
In the winter of 2005, Terri Ellsworth arrived at her son Billy’s preschool in a Pittsburgh suburb for her first parent-teacher conference. She was eager to hear how her only son, a little over 4 years old, was faring. The teachers regaled Ellsworth with anecdotes. Billy was smart; he liked difficult puzzles, music, and socializing, they said. They spread a folder of artwork and Polaroids of Billy having fun before her. But, the preschool director added in closing, there was just one thing. Billy was behind the other children in his physical abilities. In both his fine motor skills — using a fork or scissors — and his gross motor skills — running, jumping, and climbing — Billy lagged the other kids. Ellsworth had noticed it herself. Billy had been a late walker and had a lot of trouble climbing stairs. Ellsworth thought her son just lacked coordination. The preschool director, with her years of experience in early childhood development, suggested that Terri have Billy checked out.
The next four months led Ellsworth and her son to the pediatrician, physical therapists, and ultimately a neurologist who confirmed what Ellsworth and her husband — with the help of Google — had come to fear. Billy had Duchenne muscular dystrophy, a rare muscle-wasting disease that affects about one in 3,600 boys. In this form of muscular dystrophy, lack of the protein dystrophin, whose job is to hold muscle cells together, causes muscles to deteriorate. Boys and the occasional girl, typically diagnosed between the ages of 3 and 5, end up in a wheelchair by their early teens. Soon they require breathing assistance; they die in early adulthood.
The Ellsworths braced themselves for what lay ahead. “But it’s not all doom and gloom anymore,” Ellsworth recalls the doctor saying during her first appointment at Children’s Hospital of Pittsburgh’s Muscular Dystrophy Clinic. The doctor, poised to retire, explained that for the first time in his career, he was seeing promising drugs in the research pipeline. There was hope.
Billy started on standard treatment: steroids and physical therapy. But the doctor’s hopeful forecast was correct. Six years after his diagnosis, in August of 2011, Billy was among the first 12 boys in the country to begin receiving weekly infusions of the experimental drug eteplirsen, marketed by Sarepta Therapeutics as Exondys 51. Last year, through accelerated approval, Exondys 51 became the first Food and Drug Administration-approved drug to treat DMD.
Approval of Exondys 51 ignited hope, where there was none, for boys living with a rare, horrific disease. But it also ignited controversy. Approved on limited and hotly debated clinical evidence, the drug came to market under enormous pressure from patient advocates. Opponents of the drug’s accelerated approval fear it sets a dangerous precedent at the FDA: In their eyes, there is danger if patient voices drown out scientific evidence.
Mutations in the dystrophin gene — the largest gene in the genome — can prevent the gene from producing dystrophin and lead to Duchenne. Exons are pieces of DNA that, when strung together, contain the instructions for making proteins. When a mutation causes an exon to prematurely halt the translation of a gene into a protein, what’s left of the instructions can be nonsensical. But “skipping” certain exons and stringing together the remaining ones can produce instructions that are good enough to make a short protein — in this case, a weakened by still functional version of dystrophin.
For about 13 percent of people with Duchenne, skipping exon 51 can help make sense of the other exons and can lead to a more complete translation of the dystrophin gene. For other kids with Duchenne, skipping a different exon could do the trick. Exon-skipping medications, such as Exondys 51, place a “molecular patch” over the exons to be skipped.
Exondys 51 received accelerated approval in September 2016. The FDA’s accelerated approval pathway allows for drugs that treat serious conditions and address an unmet need — for example, to treat fatal conditions, such as Duchenne, for which there is no other treatment — to receive approval more quickly than those approved through the traditional pathway. Drugs achieve this approval by reaching a surrogate endpoint, that is, a marker — such as a lab reading or a scan — that researchers believe is “reasonably likely” to predict an eventual clinical benefit. The drug must later demonstrate clinical benefit in a confirmatory trial. If the trial doesn’t produce the necessary evidence, the FDA can revoke the approval.
Exondys 51’s surrogate endpoint was the production of dystrophin. “The concept is that if you could get more dystrophin expressed … then this increase should be able to change the trajectory of the disease,” says Pat Furlong, president and CEO of Parent Project Muscular Dystrophy, an advocacy group and the largest organization dedicated solely to Duchenne.
Results of the confirmatory trial are due by 2021.
A Rocky Road to Approval
Twelve boys, including Billy, participated in the U.S. clinical trials of Exondys 51. Studies of this size are not particularly uncommon when it comes to drugs for rare diseases. Remember, Exondys 51 isn’t even for all boys with this rare disease — who totaled just 349 in the U.S. in 2007 — but only for the 13 percent that have the relevant gene mutation. What’s more, only boys who could still walk were eligible for the study.
“The FDA has shown substantial flexibility in the last few decades in its review and approval of drugs for rare diseases, often approving drugs on the basis of an effect in 10 patients,” says Aaron Kesselheim, a physician and the director of the Program on Regulation, Therapeutics and Law in Brigham and Women’s Hospital Division of Pharmacoepidemiology and Pharmacoeconomics. “I think that if a drug has a transformative effect, one could theoretically observe that in a trial of 12 patients.”
But FDA scientists didn’t observe a transformative effect.
Researchers used two laboratory tests — immunohistochemistry analysis and Western blot analysis — to measure the boys’ dystrophin prior to starting the medication and at several points throughout the study.
The FDA found Sarepta’s initial tests of post-treatment dystrophin levels to be flawed and misleading. A 2013 study overstated the drug’s effects, creating unrealistic expectations among parents and leading then-FDA Commissioner Robert Califf to call for the paper’s retraction last year. Subsequent tests revealed nominal increases in dystrophin. In one study, dystrophin increased by just under 1 percent after three and a half years of treatment. In another study, still in progress when Sarepta applied for approval, dystrophin levels had increased by about 0.2 to 0.3 percent after 48 weeks.
Study investigators used a six-minute walk distance test to assess maintenance or decline of walking ability over the treatment. While some boys could still walk at the end of the study, the data didn’t prove that it was additional dystrophin that had preserved their ability. Among the four boys with the best six-minute walk distances, two of them had the highest dystrophin levels in the group, but two had levels close to zero.
“The effect of the drug to the scientific reviewers at the FDA — except the leadership — and to the majority of the advisory committee did not appear clinically relevant,” says Kesselheim.
In April 2016, after a public hearing, an external advisory committee voted 7-6 against accelerated approval. Of the six who voted in favor of the drug, it should be noted, three were consumer or patient advocates. The advisory panel made its recommendation in a ballroom before an audience of more than 1,000 people, including boys with Duchenne, some of them trial participants, and their parents. Teary-eyed children in wheelchairs looked at their parents in disbelief to make sure they had understood correctly. The families had traveled to testify about the benefits of the drug during four hours of public comment before the committee voted. Fifty-one of 52 presenters favored approval of the drug.
Billy and his mother spoke for three minutes. Then Billy demonstrated the drug’s benefits and his own strength by throwing a football to a fellow trial participant. The committee was not swayed. The final decision, however, belonged to Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research. (Woodcock declined to be interviewed for this story.)
New Course of Action
All those years ago, when Billy was 4 and attending one doctor’s appointment after another before arriving at his diagnosis, a neurologist asked Billy to jump. He couldn’t. Most children with Duchenne never develop the ability to jump. But in the winter of 2012, Billy was 11 and had been enrolled in the clinical trial since August. He was watching television with his parents, when he went upstairs to get a Matchbox car from his room.
“He came back down and jumped off the bottom step, just one step, and he stuck the landing,” Ellsworth recalls. “At 11 years old, he should have been in decline, not gaining skills.”
The mother’s first instinct was to shout the news from the rooftops — of Facebook. But she hesitated, thinking of all the Duchenne parents she knew whose children were indeed in decline, whose sad stories she read on social media every day. She then reconsidered and decided it was her duty to post.
If Billy was getting the experimental drug — they didn’t know yet whether he was on Exondys 51 or a placebo — then “it was important to show that it was working,” she says. “It’s still important to show that it’s working, that he’s still walking at 16 years old.” She posted the news on Facebook and has been outspoken on social media about the benefits of the drug ever since.
Other parents in the study weren’t surprised to learn eventually that Billy was taking Exondys 51 and not the placebo. A couple of dads had observed that Billy — who, since age 6 had walked on his toes, a characteristic of Duchenne — had begun to lower his heels. Billy could open bottles now, as well as those human-proof, hermetically sealed packages that his Hot Wheels came in. In one of Ellsworth’s 200 YouTube videos documenting Billy’s progress, the boy pours milk from a heavy gallon jug.
Billy’s life was no longer following the typical course for a boy with Duchenne. At 16, he walks, feeds, and bathes himself and goes to the bathroom on his own. In fact, 10 boys in the study still walked after five years on the drug. Ellsworth detailed all of this in a letter to FDA Commissioner Califf; she sent copies to the 535 legislators on Capitol Hill.
“We have a safe and effective drug now,” she wrote. “It would be criminal, immoral, and unethical to allow an entire generation of children to die … Please don’t let this generation of boys be the forgotten boys. I ask you to do the right thing … and to give them a chance at a better quality of life that they all deserve.”
Other parents of the study participants spoke out, too. They argued in letters, on social media, and in meetings with FDA officials that their experience wasn’t just a coincidence. The drug worked.
“Some kids are doing really, really well,” says Furlong. “And some kids are doing less well, but at the end of the day, and certainly in the years leading up to the advisory committee meeting and before a decision was made, the young men in the study continued to walk.”
Finally, a Decision
Five months after hearing the advisory committee’s recommendation, Woodcock overrode the committee and approved the drug, which is priced at $300,000 per year. (See “Why So Expensive?” page 53.) Deviations from committee recommendations are infrequent but not unprecedented. FDA leadership disregards an advisory committee’s recommendations on drug approval about 10 to 25 percent of the time, estimates suggest. Within a month of Woodcock’s decision, Ellis Unger, the director of the Office of New Drugs – Office of Drug Evaluation I within the Center for Drug Evaluation and Research, appealed the decision to the Office of Scientific Integrity, triggering a formal internal review of the process by which Woodcock had made her decision. The review was submitted to Commissioner Califf.
After reiterating doubts about the clinical benefit of the drug, the review raised the concern that Woodcock might have been swayed by excessive influence from the public, patients, advocates, and Congress. The FDA received countless letters from the public and lawmakers in support of the drug. Some of the correspondence was aggressive and peppered with expletives.
While Exondys 51 was under FDA review, Woodcock had numerous meetings with patient advocates, including boys with Duchenne and their parents, the review highlighted. A member of the drug review team who had attended the meetings described them as “intense,” “personal,” and “intimidating.”
Ultimately, Califf upheld Woodcock’s decision. He concluded that her decision was informed by her scientific expertise and that she didn’t overstep her authority in making it. He also told Forbes that it would not have been appropriate for him, a political appointee, to overrule Woodcock, a career regulator.
Some concede that patient and family involvement in the review of Exondys 51 was in line with the FDA’s push for patient-focused drug development and its call for input from patients on their condition and their treatment goals.
Parent Project Muscular Dystrophy worked with the FDA for years prior to the approval of Exondys 51 to propose guidelines on patient-focused drug development for Duchenne. “Our pilot study found that parents’ highest priority, above adding years of life, was slowing disease progression,” says Furlong. The advocacy group’s guidelines urged the FDA to emphasize drugs that could do that.
“If we get it right, using patient input to help weigh risk-benefit balance will be a better way to reach those decisions when you’re dealing with unmet medical need, where there are few or no good treatments,” says Christopher-Paul Milne, an attorney and the director of research at Tufts University’s Center for the Study of Drug Development.
Exondys 51 was hardly the first drug to ride a wave of patient advocacy all the way to approval. In recent memory, the FDA approved flibanserin for female sexual dysfunction amid enormous pressure from advocates and dubious clinical evidence in 2015.
In the end, because there weren’t safety concerns about Exondys 51, proponents assert that the FDA had to approve it to see if it would work. “We’re not going to be able to get enough information about whether these new technologies work, whether they’re cost effective, unless they’re reimbursed,” says Milne.
Critics of the decision fear it opens the door for faster approval, disproportionate patient influence, diminished scientific rigor, and runaway costs. Indeed, upon its approval, Sarepta slapped a $300,000-per-year price tag on Exondys 51, and at least one insurance company has refused to cover it.
“It doesn’t do anybody any good to approve drugs that don’t work,” says Kesselheim. “It doesn’t do patients any good, because the drug is now being sold for $300,000 a year, and patients have to figure out a way to pay for it, while using this drug may move them away from getting involved in a trial of the next drug that actually would work.”
That next drug could already be in the pipeline. Half a dozen or so medications for Duchenne — including exon-skipping drugs that target exons other than 51 — are currently in development. Whether Exondys 51, in its path to approval, will be an outlier or a precedent-setter remains to be seen.
As other drugs come down the pike, many families are still fighting to get Exondys 51 for their sons. Insurance companies don’t want to cover it for boys who’ve already lost their ability to walk, but advocates like Ellsworth argue that the drug can still slow the disease; she continues to fight for those families. “Wouldn’t you want this drug as a lifeline if this were your child or your grandchild? It’s my responsibility to do what I can do,” she says. “This drug works, and more boys deserve it.”