FDA panel votes against Sarepta's Duchenne muscular dystrophy drug

Sarepta Therapeutics' shares plunged as much as 40 percent Tuesday after an FDA advisory committee voted 7-3, with three abstentions, that a study involving 12 patients did not provide substantial evidence that the company's experimental drug eteplirsen is effective as a treatment for Duchenne muscular dystrophy amenable to exon 51 skipping. Panel member Richard Kryscio, who voted against the injectable therapy, said "I was not convinced the data was there to prove something based on one, poorly controlled study."

Documents released last week ahead of the meeting reiterated earlier concerns about the company's application, with FDA staff raising issues surrounding trial data for eteplirsen, including the small number of patients tested, the drug's effectiveness and Sarepta's statistical analysis. At the meeting, the majority of panelists noted that Sarepta's study was not adequate or well controlled enough to demonstrate that eteplirsen was responsible for some of the benefits claimed by patients.

"Know that if these results were from a well designed and interpretable trial, there likely wouldn't be much to talk about," commented Billy Dunn, director of the division of neurology products in the FDA's Center for Drug Evaluation and Research (CDER). However, Janet Woodcock, head of the agency's pharmaceutical division, remarked that while it was hard to know whether the therapy conferred a benefit, the consequences of failing to approve a drug that actually works in devastating diseases were "extreme" and borne by the patient.

Although panelists acknowledged anecdotes from several boys with the disease who said eteplirsen had helped them maintain their strength, a majority of experts suggested that those results were not reflected in Sarepta's data. "Unfortunately, what I would consider meaningful evidence from the testimony of the families is not properly measured in the study," remarked panel member Chiadi Onyike.

The advisory committee was also asked whether Sarepta had proven that eteplirsen induces production of dystrophin to a level reasonably likely to predict a clinical benefit, a measure needed for the company to win accelerated approval of the drug. The panel voted 7-6 that it had not. Patients' average dystrophin levels on eteplirsen rose from 0 to 0.9 percent of normal levels, an increase that was "very disappointing," said Eric Bastings, deputy director of the division of neurology products in the CDER.

Bastings commented there is "no apparent correlation between muscle levels of the protein dystrophin and a change" in the boys' performance on a six-minute walk test. The FDA noted that for much of the study, doctors knew who received the drug. The agency suggested that as a result, the children's performance on the walk test could have been "influenced by expectation bias, motivation and coaching." The FDA noted that it had "strongly encouraged" Sarepta to "conduct an adequately powered, randomised, placebo-controlled trial(s) to assess the clinical effect" of eteplirsen.

In response to the vote, Sarepta's interim CEO Edward Kaye said "we appreciated the opportunity to present our data to the advisory committee panel and will continue to work with FDA as they complete their review." The regulator is scheduled to make a decision on whether to approve eteplirsen by May 26.

For related analysis, see ViewPoints: Sarepta's AdCom - plenty of emotion, not enough data.

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