In a close 7-6 vote, a committee of medical experts said today that eteplirsen, a drug to treat Duchenne muscular dystrophy, has not met the bar set by the FDA for approval, which could make the drug the third Duchenne treatment in recent months to face FDA rejection, adding to the frustration of a tight-knit and increasingly desperate community of patients and their advocates.
The committee, one of many that help the FDA evaluate drugs for approval, wrestled today with a question that, in most other circumstances, would never even merit consideration: Should the agency approve a drug based on one trial with just 12 patients?
But the consideration was serious because Duchenne is a progressive, fatal disease with no effective treatments or cure. A throng of patient advocates and others more than 1,000 strong showed up, with more than 50 making their case at today’s hearing in Hyattsville, MD, a suburb of Washington, DC, that lasted more than 11 hours. Even the FDA’s top drug official made a rare appearance at the meeting, weighing in with comments just before the vote.
Still, near-term approval of eteplirsen, developed by Cambridge, MA-based Sarepta Therapeutics (NASDAQ: SRPT), appears unlikely. The recommendations of FDA advisory panels are not binding, but the agency typically sides with the experts’ decisions.
The 13-member panel voted 7 to 6 that Sarepta hasn’t provided “substantial evidence from adequate and well-controlled studies” that eteplirsen helps Duchenne patients’ bodies create enough dystrophin—the muscle-protecting protein they lack—to predict a benefit. Just before the vote, Janet Woodcock, the director of the FDA’s center for drug evaluation and research and a key decision maker on drug approvals, made clear that the matter at hand was “accelerated approval,” a process that allows the agency to green light drugs on a thinner body of evidence.
The FDA’s final decision, due by May 26, will have significant implications for both the drug industry and thousands of patients with Duchenne. Approval risks setting a precedent for allowing drugs onto the market with a bare minimum of human testing. A rejection means patients whose disease is a death sentence lose more time before a medicine is available.
“I respect the FDA’s caution in setting a precedent in approving new drugs. But our kids are not a precedent, they are real, live human beings, and they are short on time,” said Debra Miller (pictured above), the CEO of the nonprofit Newport Beach, CA, organization CureDuchenne, at the hearing. “An FDA official once told me, ‘The worst thing we can do is approve a drug and then have to pull it off the market.’ I argue that the worst thing we can do is deny access to a drug and then find out it works—too late, after we have lost a generation of children.”
The implications of this panel were clear from the start. William Dunn, the director of the agency’s division of neurology products, noted that regardless of how urgently a drug is needed for Duchenne, the FDA would not lower its approval standards, nor would it take “perverse delight” in rejecting a drug. He knew what was coming.
“Emotions will run high,” Dunn said.
Children with Duchenne, their parents, doctors, and even some politicians spoke, nearly all pleading for the agency to approve the drug. One young patient, responding to the agency’s criticism of eteplirsen’s effectiveness, called the drug “amazing” and “life changing.”
“I can only guess you don’t know anything about Duchenne,” he said, as applause rang out.
While the panel voted against eteplirsen, Woodcock’s comments seemed to leave the door open for more evaluation. “In devastating diseases the consequences of [an unwarranted rejection] can be extreme,” she said. “But most of these cons are borne by the patients.”
That said, the agency has already brushed patient and advocate pressure aside in rejecting two other Duchenne drugs that were close to approval. In January, the agency said no to drisapersen, a drug from BioMarin Pharmaceutical (NASDAQ: BMRN). A month later, it rejected an approval application from PTC Therapeutics (NASDAQ: PTCT) on a drug called ataluren.
Both drisapersen and ataluren are meant to slow the grim march of Duchenne in certain subgroups of patients. The disease affects about 300,000 people worldwide, primarily boys, typically robs them of the ability to walk by their teens, and eventually kills them through one of a number of complications, like respiratory or heart failure.
Despite the pressing need for a Duchenne therapy, data from the BioMarin and PTC drugs just weren’t good enough for regulators. The agency called BioMarin’s drisapersen data “inconsistent and in some cases contradictory” and said PTC’s ataluren application was “not sufficiently complete to permit a substantive review.”
Both drugs had failed Phase 3 clinical trials, but the companies claimed that post-hoc analyses showed the drugs were benefitting patients.
Since the February rejection of PTC, all eyes have been on Sarepta, whose eteplirsen is also meant to slow the progression of Duchenne in a subset of patients—a group with a specific genetic mutation, about 13 percent of those with the disease. Sarepta’s original January date with the advisory committee was postponed by a snowstorm. But as with PTC and BioMarin, Sarepta faces an uphill battle, because the FDA has been just as critical of the eteplirsen data.
Indeed, prior to today’s panel, analysts were highly skeptical of eteplirsen’s chances. In research notes, Jefferies analyst Gena Wang called approval a “low probability,” while RBC Capital Markets analyst Simos Simeonidis wrote that he expected a rejection. That’s because the agency has twice skewered Sarepta’s data, first in a set of briefing documents the FDA posted in January, then again last week in an update to the documents.
The reason for the skepticism is Sarepta’s data comes from a 12-patient, Phase 2b study. In that study, the boys were split into three equal-sized groups and given weekly infusions of a low or high dose of eteplirsen, or a placebo. After 24 weeks, the placebo patients were crossed over to one of the two eteplirsen doses. The goal was to show these boys were producing more dystrophin and walking farther than they would have without treatment.
Making the sample size even smaller, Sarepta excluded two of the 12 patients who lost their ability to walk early on. Sarepta argued that their disease may have already been too far along to benefit from any drug therapy.
Sarepta is making the case for eteplirsen with the remaining 10 patients who, after some four years on eteplirsen, are still able to walk, and that these patients are doing much better than they would otherwise, based on historical data the company has accrued. This is an important point: The gold standard of clinical trials is to build a study that compares patients on a drug with those on a parallel track without the drug. But Sarepta has chosen to compare eteplirsen patients on its drug with patients from a different time period who might or might not have resembled the eteplirsen patients. That decision was made for two reasons. First, Sarepta didn’t have the resources several years ago to start a placebo-controlled trial. Then, when it finally had the resources, ethical problems emerged. As Christine McSherry, founder of the nonprofit Jett Foundation, said at the hearing, “We saw signs the drug was working,” which would have made a trial in which half the kids take placebo an untenable situation.
Sarepta’s unusual trial design isn’t unprecedented for rare disease treatments. For instance, the company has pointed to the 2006 FDA approval of Genzyme’s alglucosidase alfa (Myozyme) for Pompe disease, a decision based on a study that compared the drug’s effects to a “historical control”—that is, a database of patients deemed to have similar characteristics to those who took the drug in Genzyme’s trial.
Still, the FDA has been highly skeptical of eteplirsen’s results, and that skepticism continued today. At the hearing, the FDA’s scientists called Sarepta’s trial an “apples to oranges” comparison, citing potentially critical differences between the eteplirsen patients and control group. In a hostile environment, the agency’s clinical review team—led by Ronald Farkash and Eric Bastings—told the crowd they “haven’t heard the whole story.”
“My role, regardless of the pressure that has been placed on my division—and on the eteplirsen review team—is to present for scientific review conclusions about [the data]. We are a science-based organization,” Bastings said. “Accelerated approval cannot be used to compensate for weak or inconsistent clinical findings.”
The majority of panelists sided with the FDA scientists. One panelist, University of Texas-Houston Medical Center neurology professor Nicole Gonzales, called the data “problematic.” Harvard Medical School professor Aaron Kesselheim said the study was “not adequate or well controlled.”
Chiadi Onyike, a psychiatry professor at Johns Hopkins University School of Medicine, said the data don’t draw a clear connection between the drug helping patients make more dystrophin and actually having a benefit. “I can’t get from dystrophin production, even if I accept it, to clinical effect,” Onyike said.
Sarepta brought the controversial data to the FDA for complex reasons. Under former CEO Chris Garabedian, Sarepta triggered the hopes of patients and advocates with promising Phase 2b data in 2012. With their encouragement, Garabedian felt Sarepta could ask for accelerated approval, then a new process, with a smaller data set.
Instead of a fast-track approval, Sarepta has since been on a regulatory roller-coaster. After much back-and-forth and delay, Garabedian resigned in April 2015 amidst a reportedly contentious relationship with the FDA. (Chief medical officer Ed Kaye is now interim CEO.)
Sarepta eventually started a larger late-stage trial in September, but that won’t read out for another few years. (Like the one under review today, it is not placebo-controlled.)
That’s a concern for another day, however. For now, it’s all about whether accelerated approval is still an option, and what it would mean for Duchenne patients and Sarepta one way or the other.
“To cure Duchenne, we will probably need a combination of therapies to treat the whole disease,” Miller said. “But we cannot test drug combinations until the first drugs are approved.”