The FDA approved Monday the first drug ever for Duchenne muscular dystrophy, but only after the commissioner had to settle a high-stakes dispute between powerful agency scientists.
Prominent members of the FDA’s drug-review staff, fearful of setting a precedent for the regulation of drugs for rare diseases, voted to reject eteplirsen (Exondys 51), from Cambridge, MA-based Sarepta Therapeutics (NASDAQ: SRPT). They were overruled by the agency’s top drug evaluator, Janet Woodcock, but appealed her decision and lodged other complaints to Commissioner Robert Califf. Califf gave eteplirsen the green light nonetheless.
Sarepta said late Monday that eteplirsen would cost an average of $300,000 a year—a net price based on the patient’s weight.
In a nod to what he called “sensitivity” around drug prices, Sarepta CEO Ed Kaye said on a conference call the company was trying to be “as thoughtful as possible” and factored in the company’s past and future R&D, a commitment to develop drugs for other subtypes of Duchenne patients, and the money it will spend on studies required by the FDA.
As a reward for bringing a drug for a rare pediatric disease to market, Sarepta also receives an FDA voucher to speed up the review of another drug. Officials said today they would look to sell it to another drug maker. Similar vouchers have sold for as much as $350 million.
The company must also navigate FDA demands for more data if it wants to keep eteplirsen on the market. Sarepta must run an additional two-year, randomized, controlled trial, and that those results would determine whether eteplirsen will get pulled from the market or not. Sarepta has to complete the trial by November 2020 and must submit final data from that study the following year.
Getting to market at all seemed in recent months a long shot, at best. But not only did Califf side with Woodcock and overrule other scientists, he also provided a full-throated defense of Woodcock, who was accused by her colleagues of being swayed by “external pressures” from patient advocacy groups and Congress, and of meddling in the review process.
“A review of Dr. Woodcock’s record reveals extraordinary courage in the face of extreme pressure on many occasions, including from Congress, the press, patient and patient advocacy groups, and industry,” Califf wrote. “She has taken and supported unpopular decisions when appropriate and is well known for not relenting to pressure.”
It’s all made for a “big day of celebration” for Duchenne patients and their families, says Debra Miller, the CEO of nonprofit group CureDuchenne. “It’s been a very long and rocky road,” Miller said. “It’s encouraging to see that the FDA can be and is going to be flexible.”
With no approved therapies until today, Duchenne, a rare genetic muscle-wasting disease, typically puts boys diagnosed with it in wheelchairs by their teens and kills them by their 20s. Eteplirsen is meant to slow the progression of the disease in the 13 percent of patients whose Duchenne is caused by a specific genetic mutation. (Miller says CureDuchenne provided a financial grant to Sarepta in 2010, and that the company has supported educational events CureDuchenne has run, but the group has no other financial ties to the company. Sarepta CEO Kaye is on CureDuchenne’s scientific advisory board.)
The drug’s review has become a test case for the increasing power of patient advocates like Miller’s group and their impact on drug development and approvals. Leerink Swann analyst Joseph Schwartz wrote in a note to clients that other rare-disease drug developers should feel more optimistic “based on the extreme regulatory leniency shown by the FDA toward eteplirsen.”
Public hearings on eteplirsen and a drug rejected in January by the FDA, drisapersen, have seen throngs of patients and advocates pleading with regulators to approve these experimental drugs despite flawed data. “This shows that the FDA in this case is willing to make decisions on pretty skimpy evidence,” says Joel Lexchin, a professor emeritus at York University’s school of health policy and management in Toronto. “This opens the door increasingly for decision-making based on politics and emotions, rather than science.”
More than 50 patients spoke at Sarepta’s hearing, and all but one begged for eteplirsen’s approval. Despite the showing, a panel of outside experts recommended 7 to 6 that the FDA reject the drug. FDA officials at Sarepta’s hearing in April made unusually pointed comments about the negative effect of advocates’ emotional appeals. The FDA document released today echoed those comments, and added criticism of Sarepta for its role stoking enthusiasm without proper data. The document also noted that Woodcock had worried in meetings that without an accelerated approval, Sarepta wouldn’t have the money to continue running trials on eteplirsen or other experimental Duchenne drugs. Califf, in his defense of Woodcock, said he asked her about her statements and was satisfied that “her decision is indeed based on her scientific evaluation of the evidence.”
Outside observers wanted more clarity.
“The one thing I would want to know was whether any member had a conflict of interest,” said Sheldon Krimsky, an adjunct professor of public health and medicine at Tufts School of Medicine. “This has happened in the past. It should be public information.”
Until a few months ago, the only data the FDA had on eteplirsen were from a tiny, 12-patient clinical trial. Those scant data compared patients on eteplirsen to a “historical control”—previous data on patients deemed to have similar characteristics to those who took the drug—but not to patients receiving a placebo in the study, which the FDA prefers. The agency’s clinical review team skewered Sarepta’s data, which they claimed didn’t provide the support needed to approve eteplirsen. Many sell-side analysts covering Sarepta gave eteplirsen little chance at approval. That’s why Sarepta’s shares shot up more than 70 percent when news of the thumbs-up broke on Monday.
Ellis Unger, director of the FDA’s office of drug evaluation-I, Luciana Borio, the FDA’s acting chief scientist, and John Jenkins, the director of the agency’s office for new drugs, all disagreed with Woodcock’s approval decision. Instead of the commissioner having final say, Lexchin argues that an independent person or entity should resolve cases that have “such a level of disagreement.”
The rift centered upon a protein, dystrophin, that Duchenne patients cannot produce. Woodcock and colleagues disagreed whether the dystrophin boost that eteplirsen produces is an adequate predictor of its eventual benefit to patients.
Part of the problem was flawed studies. Early data and anecdotes, publicized by Sarepta, turned out to be inaccurate. But they had already “fueled the public perception that eteplirsen is highly effective” as well as patients’ reluctance to participate in placebo-controlled trials, Unger wrote.
According to the FDA document, Woodcock recognized Sarepta’s studies were flawed, but she didn’t want to hold those flaws “against the patients.”
Woodcock’s staff questioned how much the pressure from politicians, patients, and advocates influenced her thinking. One of her staffers, left unnamed in the FDA document, said that her views “were not always clear during discussions throughout the review of the science—sometimes she seemed to agree with external constituents, sometimes not.”
Leaning more heavily on the needs and wishes of patients could soon gain greater traction at the FDA. Woodcock is a key proponent of more patient-centric drug evaluation. She is also a central figure in the political tussle to renew, by Congress every five years, the funding the FDA uses to pay for its drug reviews. (The money comes from fees paid by drug companies.) The current authorization ends in 2017. The renewal, called PDUFA in shorthand, is also a window to make changes, sometimes broad, sometimes minute, to the drug side of the FDA.
At a public meeting last month to discuss the upcoming renewal, Woodcock stumped for “tools that will enable patient groups, other stakeholders, the FDA, to collect meaningful patient input on what really matters to them as far as drug therapeutics so that we understand and regulators are applying a benefit-risk calculus that really reflects the position of the patients, what burden of disease means to patients, what relief they are seeking, what different adverse events mean to them, and so forth.”
Advocates for patients with other rare diseases have watched the Duchenne proceedings closely. Kenneth Hobby, the president of Cure SMA, which advocates for patients with spinal muscular atrophy, said that the eteplirsen ruling appears to signal a “new, more flexible and favorable viewpoint to the process for approval of therapies for rare diseases.”
“It will be interesting and important to see how the FDA will take this precedent and now apply it to other diseases,” he said. For the first time, an experimental therapy for SMA could be up for FDA approval next year.
In his eteplirsen decision, Califf was careful to write that no precedent is being set, and that each drug “must be evaluated on its own merits based on the totality of data and information.” But others at the FDA weren’t so sure.
Unger wrote that eteplirsen’s approval could have “profound” ramifications and “send the signal that political pressure and even intimidation—not science—guides FDA decisions, with extremely negative consequences.”
The FDA’s review team said it received many letters from the public and Congress, and some of them “used vulgar language and [were] abusive to the review staff.” At least two members of the agency’s review team left, or were leaving the agency because of those pressures and the scientific tug of war at the FDA. It’s unclear if the document was referring to Ronald Farkas, the head of the FDA’s eteplirsen review team. News surfaced last week that he had left recently. Farkas wasn’t named in the document released today, but CureDuchenne’s Miller said that when Farkas left, she “started feeling a lot more positive” about eteplirsen’s chances.
—Alex Lash contributed to this report