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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.