In setback, a majority of FDA experts reject Sarepta’s emotional campaign to gain Duchenne drug OK

Sarepta lost a major battle in its years-long quest to gain an accelerated approval for its Duchenne muscular dystrophy drug eteplirsen.

An FDA panel of outside experts voted 7 to 6 that Sarepta did not provide substantial evidence from “adequate and well controlled” studies that the drug produced dystrophin at a level that was reasonably likely to produce a clinical benefit. Seven of the agency advisers also voted that there could not be an objective, valid comparison that was free of bias between patients receiving eteplirsen and a historical control group that was used to demonstrate efficacy.

Then there was the full approval question. Do the clinical results of the single study provide “substantial evidence” of eteplirsen’s efficacy?

Again, 7 panel members voted no, with three voting yes and three abstaining. 

On Wednesday morning, Sarepta's shares plunged 45% in premarket trading, continuing the roller coaster ride that some investors have been on for some time now. RBC's Simos Simeonidis, who was skeptical going into the vote, expects that it wll be much easier now for the FDA to issue a formal rejection of marketing approval.

Joseph Schwartz at Leerink noted that it was the panel members with the greatest expertise in the field who lined up against the drug. "Ultimately, some ~900 pt. advocate attendees were once again left frustrated and upset at the rigidity of the FDA panelists precipitating in a heated outcry against Dr. Chiadi U. Onyike," he noted, "who recommended that the community support a placebo controlled trial going forward."

Sarepta stumbled on crucial questions regarding the drug’s ability to safely tap the brakes on DMD, which the advisory committee considered after FDA insiders and Sarepta supporters outlined starkly different views of eteplirsen and the data used to support an accelerated approval. 

The vote came after a grueling 11-hour session during which a large crowd of patients and drug advocates lent a loud and emotional voice demanding that the agency go ahead with an accelerated approval for marketing the drug in the U.S.

From the start, Sarepta balanced its position on the data with an emotional, sometimes tearful, call for a positive response to their drug.

"I can't see any grounds for denying this drug for DMD boys,” said Jerry Mendell, the principal investigator in the key study under review, whipping up cheers from the largely pro-eteplirsen crowd.

In an extremely unusual twist for an FDA panel review, Sarepta execs quickly handed the podium over to Duchenne drug activist Christine McSherry, who presented video clips of some of the boys recruited for the study. Those testimonials might be viewed as entirely anecdotal by experts, but they’ve proved powerfully persuasive for the advocacy community, especially the parents who have to watch helplessly while their sons are slowly crippled and then killed by DMD.

Her testimony and videos were greeted by whoops and cheers, something else you don’t hear much of during FDA panel reviews.

After a cautionary remark from the FDA’s Janet Woodcock, who encouraged the committee to weigh a need to avoid erroneously endorsing drugs that might not be effective while remaining sensitive to the need of OKing a drug that might work, the hearing offered two radically different conclusions on one drug.

Agency insiders repeated a harsh assessment of Sarepta’s data, insisting that the company repeatedly ignored its advice on the right way to run a study on this drug. A late revision failed to provide convincing data that the drug did what it was designed to do: significantly increase dystrophin, the lack of which clearly triggers the fatal disease.

Repeatedly, the regulators highlighted the suspect results cited by Sarepta in its pursuit of an approval. In particular, the agency officials noted a questionable use of an inappropriate historical control group, even though there were stark differences between the data gathered from patients in earlier studies and the data on patients in their own, limited clinical study. 

There are "reasons to be concerned this was not an appropriate control to pick,” noted the FDA’s Ronald Farkas, highlighting how investigators improperly compared dystrophin levels in different types of muscles. 

In addition, the regulators noted that the company has repeatedly spotlighted major efficacy results that were never borne out by credible data. And they added that the biotech ignored repeated instances when the agency underscored the need for larger, decisive trials that could provide solid evidence of success or failure.

Added up, the regulators' remarks created enough doubt to sway the vote against eteplirsen.

Dozens of parents and Duchenne kids, though, weren’t buying it. They insisted that the drug was working and offered this vulnerable group of dying kids their only chance of extended survival, their only chance of more hugs, more love and more hope for the future.

The FDA’s skepticism, for patients and their families, represents a simple denial of the obvious. And the patients’ hope, for the FDA, represents a simple human devotion to wishful thinking in the face of a nightmare. 

The final decision on eteplirsen's immediate fate now passes to the FDA. Sarepta, meanwhile, is pursuing a pivotal study that won't read out until 2019.

The last few months have proven to be excruciating for patients and families, who currently have nothing to turn to to slow or stop a disease that first cripples and then kills boys. BioMarin tried and failed with drisapersen, with an FDA rejection landing in January. PTC Therapeutics never made it through the door with their therapy, as regulators refused to even file an application they found too weak to warrant careful consideration. And now, barring a last-minute surprise, it looks like Sarepta's eteplirsen faces the same fate.