[Updated 9/19/16, 12:42 p.m. See below.] In a decision that could have myriad implications for both the pharmaceutical industry and patients with Duchenne muscular dystrophy, the FDA today approved a drug called eteplirsen from Cambridge, MA-based Sarepta Therapeutics (NASDAQ: SRPT). With the FDA nod, eteplirsen has become the first drug ever approved for Duchenne, a progressive and fatal genetic disease, and potentially has set a precedent for drug approvals in the U.S.
The approval came from the very top of the agency. Commissioner Rob Califf stepped in and gave the green light after top drug-review officials clashed over eteplirsen’s merits.
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—not to patients receiving a placebo in the study, which the FDA prefers.
This is typically the type of data that wouldn’t even get a look from the FDA, but a number of factors changed the equation—among them political pressure, a mobilized patient group, a lack of approved treatments, and the agency’s rejection of two Duchenne drugs this year already.
The FDA showed flexibility, and eteplirsen became an unusual case. Though a committee of experts in April voted against approval, the FDA didn’t immediately follow with a decision. In early June, the FDA instead asked for more data: 13 muscle biopsies from an ongoing Phase 3 trial. The request was a compromise. The FDA could make a decision based on information from 25 patients, not 12. And Sarepta and Duchenne patients wouldn’t have to wait years for results from a larger trial. If the biopsies showed enough evidence that eteplirsen was helping Duchenne patients produce dystrophin—the muscle-protecting protein they lack—the FDA would approve the drug. If not, eteplirsen would be rejected.
In an announcement Monday morning, the FDA approved eteplirsen on an “accelerated” basis, or on a thinner body of evidence than is typically required. In the statement, the FDA said that it has concluded that the data submitted by Sarepta “demonstrated an increase in dystrophin production” that is “reasonably likely” to predict a benefit in a subgroup of patients with the disease.
The FDA cautioned, however, that eteplirsen has not yet proven a real clinical benefit, and that Sarepta has to conduct an additional trial to show that benefit exists. If the trial fails, the FDA may pull eteplirsen from the market. “In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy,” the agency said in its statement.
“Patients with a particular type of Duchenne muscular dystrophy will now have access to an approved treatment for this rare and devastating disease,” added Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research, in the statement. “In rare diseases, new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders. Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval.”
[Updated with details from an FDA document.] According to an FDA document, Woodcock decided to approve eteplirsen, but other key decision makers —Ellis Unger, director of the FDA’s office of drug evaluation-I, and Luciana Borio, the FDA’s acting chief scientist—appealed her decision to commissioner Califf. Unger questioned Woodcock’s deep involvement in the drug’s evaluation. She told the board that mediates disputes that she was leaning toward approval as early as 2014, according to the document.
Califf noted that it is “highly unusual” for a drug application to be appealed to the commissioner’s office, but he ultimately sided with Woodcock. He expressed confidence that this “unique situation” wouldn’t set a precedent for drug approvals.
Shares of Sarepta soared nearly 80 percent on the news, trading at over $50 apiece early Monday.
It’s unusual but not unheard of for the FDA to go against its own advisory panels. The female sexual enhancement drug Addyi was rejected by a panel before the FDA approved it last year, for instance. Still, eteplirsen’s saga has been anything but typical.
The FDA this year has already rejected two experimental drugs for Duchenne, a progressive, fatal disease with no effective treatments or cure. Eteplirsen—though only meant for patients with a specific genetic mutation, about 13 percent of those with the disease—was the next to the feet of the FDA. “To cure Duchenne, we will probably need a combination of therapies to treat the whole disease,” Debra Miller (pictured), the CEO of the nonprofit CureDuchenne, told Xconomy in March. “But we cannot test drug combinations until the first drugs are approved.”
Still, by approving eteplirsen, the FDA might be setting a precedent for allowing drugs onto the market with a bare minimum of human testing. What’s to stop other developers of drugs for rare diseases, supported by mobilized patient communities, from trying to win approval on flimsy data? What if that ends up bringing drugs to market that shouldn’t be there, and lead to safety issues? What if the FDA later has to pull eteplirsen from the market when new data emerges? As Xconomy reported last month, for instance, advocates for patients with another rare disease, spinal muscular atrophy, have been watching the proceedings closely. As Kenneth Hobby, the president of the nonprofit group CureSMA, said at the time: “Whatever [the FDA does] there is going to set a precedent for other orphan therapeutics coming through,” Hobby says. “It’s going to have to be the benchmark for other diseases, like SMA.”
This issue is sure to stir debate in the months and years to come. But today marks a celebration for Duchenne patients who have waited years for an approved drug. Eteplirsen doesn’t cure Duchenne, but it is supposed to slow the grim march of the disease, which puts most patients in wheelchairs by their teens and kills them—typically from heart or lung complications—by their mid-20s. Duchenne affects about 300,000 people worldwide, primarily boys.
Despite the pressing need, the FDA rejected drugs from BioMarin Pharmaceutical (NASDAQ: BMRN]) and PTC Therapeutics (NASDAQ: PTCT) earlier this year. The agency called BioMarin’s data for drisapersen “inconsistent and in some cases contradictory” and said the application for PTC’s ataluren was “not sufficiently complete to permit a substantive review.”
In the eteplirsen study, 12 patients were split into three groups of four. They received either a weekly infusion of eteplirsen at a low dose or a high dose, 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.
Shrinking the sample size further, Sarepta excluded two of the 12 patients who lost their ability to walk early on. Sarepta argued that their disease might have been too far along to benefit from any drug therapy.
Sarepta initially sought approval of eteplirsen with the remaining 10 patients who, after some four years on the drug, are still able to walk. Sarepta said 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 compared eteplirsen patients to a historical control—patients from a different time period who were deemed to resemble the eteplirsen patients. Sarepta has said it did not run a large, placebo-controlled trial because of limited finances and ethical reasons.
It’s not unprecedented for a drug to be approved based on a study comparing a drug’s effects to a historical control. The FDA approved Genzyme’s alglucosidase alfa (Myozyme) for Pompe disease in 2006, for example.
But the FDA was highly skeptical of the eteplirsen data and Sarepta’s measurements. FDA scientists called Sarepta’s trial an “apples to oranges” comparison, citing potentially critical differences between the eteplirsen patients and control group.
“We are a science-based organization,” said Eric Bastings, a member of the FDA’s clinical review team, at the hearing. “Accelerated approval cannot be used to compensate for weak or inconsistent clinical findings.”
University of Texas-Houston Medical Center neurology professor Nicole Gonzales, a member of the advisory panel that recommended an FDA rejection, called the data “problematic.” Harvard Medical School professor Aaron Kesselheim said the study was “not adequate or well controlled.”
Still, Woodcock seemed to leave the door open for approval. When The Food and Drug Administration Safety and Innovation Act was signed in 2012, she said at the hearing, U.S. congress “urged” the FDA to approve drugs on an “accelerated” basis more “broadly,” particularly in the cases of rare diseases. She openly talked about the consequences of a “type 2 error”—failing to approve a drug only to find out later on that it worked. “In devastating diseases the consequences of [an unwarranted rejection] can be extreme,” she said. “But most of these cons are borne by the patients.”
With the FDA’s decision today, that sentiment appears to have won out.
Check out these stories for more on Sarepta and eteplirsen’s roller coaster ride, and the back-and-forth between the company and the FDA.