The question of whether Sarepta Therapeutics could file for FDA approval of its Duchenne Muscular Dystrophy drug based on a tiny, yet promising set of data from a mid-stage clinical trial has been one of the biggest biotech questions of the year. The FDA provided the answer today, and it wasn’t the one the Cambridge, MA-based company had been hoping for.
Sarepta said today that the FDA has changed its stance and deemed its new drug application for its DMD drug candidate, eteplirsen, “premature,” meaning that as of now, the company will have to go the traditional route and put together a large, confirmatory Phase III study before it can win approval for regulators. It’s a big setback for Sarepta, which had been hoping that the promising results from its 12-patient mid-stage study would be strong enough for the FDA to consider approving the drug and was told the agency was “open” to considering an application in July.
The FDA decision means that Sarepta won’t be able to start a Phase III trial until at least the second quarter of 2014, and potentially delays approval of eteplirsen by two years or more. Shares plunged more than 50 percent on the news. The company was clearly stunned by the FDA’s change of opinion, and intends to keep the dialogue open in the hope that it can convince the agency to reconsider. Sarepta will have another meeting with the FDA later this month.
“We do not fully understand, nor do we agree with the FDA’s new stance or with its comments,” said Sarepta CEO Chris Garabedian on a conference call with analysts this morning. “We believe the door is open for them to reconsider this.”
So why the change of heart from the FDA? Sarepta mentioned two specific reasons. First, Sarepta says that the FDA has been swayed by recent clinical failures in the Duchenne field. GlaxoSmithKline and Prosensa’s rival drug, drisapersen, crashed in a big, Phase III clinical trial earlier this year, and another Duchenne drug candidate from PTC Therapeutics has also failed trials in the past. Eteplirsen, like the Glaxo/Prosensa and PTC drugs, is designed to help boys produce the dystrophin proteins their muscles need to properly function. So the recent failures have raised “serious doubt” that increased production of dystrophin can serve as an acceptable surrogate endpoint for approval of the drug, the FDA said.
Secondly, the FDA has said that recent data suggest that a boy with Duchenne’s ability to walk more than 350 meters at the beginning of a standard 6-minute walk test predicts “general stability” for those patients. That is in contrast to the 75- to 83-meter yearly decline Sarepta has suggested as a benchmark based on historical figures. The FDA believes the new data have called into question the results Sarepta’s drug has achieved in its Phase II trial, because all of the patients in its study could walk more than 350 meters when they started taking eteplirsen.
The FDA has recommended that Sarepta should consider looking at other study goals or populations in its next trial, and that “many possible combinations of endpoints and subpopulations” may be sufficient. It suggested that a placebo-controlled trial—in which one group is randomly assigned a placebo, and the other Sarepta’s drug—is most likely the best way to provide “interpretable evidence” that eteplirsen works.
Sarepta, now, is going to do two things: one, try to change the FDA’s mind, and two, figure out exactly how to structure a Phase III study. Garabedian noted on the call that there are significant logistical challenges to putting together such a study. The population of Duchenne patients, for instance, is already small, and the ones with the specific genetic abnormality that eteplirsen targets is even smaller. Sarepta will have to roughly double the group of potential enrollees in its next study to account for a placebo group. It’s hoping to come to an agreement with an FDA on the structure of the trial.
Eteplirsen is an RNA-based drug that targets an abnormality in part of the dystrophin gene called exon 51, and helps patients skip past the faulty section of the gene so they can make enough of the protein to keep their muscles working. About 13 percent of Duchenne patients have the form of the disease caused by this particular genetic variation. Sarepta’s plan has been to establish a franchise in Duchenne by moving drugs forward behind eteplirsen that target a different genetic variation triggering Duchenne, and then being able to get them approved on their ability to increase dystrophin production alone. At best, if the FDA decision stands, this will now take much longer than Sarepta had hoped.
“We believe this setback does not reduce the chance of ultimate approval of the drug,” Garabedian said on the call. “We will pursue a more traditional path to approval while we concurrently try to persuade the FDA to reconsider the potential of an early filing strategy for eteplirsen.”
Duchenne is a progressively disabling, deadly neuromuscular disease that robs boys of their ability to walk and function. There is no approved cure for the disorder.