Sarepta Therapeutics Inc. disclosed Monday afternoon following the market's close that the FDA has asked for additional information from its existing eteplirsen dataset before making a determination about a new drug application (NDA) filing for the drug under Subpart H accelerated approval.

Sarepta said the agency's feedback was provided in minutes from an end-of-Phase II meeting with the Division of Neurology Products last month about the exon-skipping drug candidate, which Sarepta is studying in Duchenne's muscular dystrophy (DMD).

Specifically, the FDA asked for additional information on the acceptability of dystrophin – a protein that plays a key structural role in muscle fiber function – as a surrogate endpoint that would reasonably predict clinical benefit in DMD patients and the acceptability of the eteplirsen safety database for an accelerated approval filing.

Eteplirsen uses Sarepta's phosphorodiamidate morpholino oligomer (PMO)-based chemistry and skips exon 51 of the dystrophin gene, enabling the repair of genetic mutations that affect approximately 13 percent of the DMD population.

In a call with analysts late Monday, Chris Garabedian, president and CEO of the Cambridge, Mass.-based biotech, characterized the FDA's request for more data as "a reflection of the thorough and comprehensive approach the agency takes in evaluating a new surrogate marker."

Sarepta is confident "that the method in which we've collected dystrophin, the degree and consistency of the dystrophin levels and the supporting clinical data will provide the agency the information it needs," Garabedian said.

Still, the specter the FDA could potentially require a larger Phase III trial prior to NDA filing made investors nervous. Sarepta's shares (NASDAQ:SRPT) opened 12 percent lower Tuesday morning and failed to gain ground during the day, closing at $33.99 for a loss of $5.25, or 13.4 percent. Volume was four times heavier than average.

Analyst: Sarepta 'Surprised' by FDA's Request

In its end-of-Phase II meeting with the FDA, Sarepta addressed in detail the suitability of dystrophin as a surrogate marker, explaining the methodologies used to analyze dystrophin in the studies and reviewing data suggesting that the dystrophin produced is functional, according to Garabedian. In the meeting minutes, the FDA essentially requested written summaries from the company on both topics.

"Make no mistake: We had a lengthy and detailed amount of information in the briefing document," Garabedian said. Although such documents usually provide sufficient information for the agency to make a decision, "it is clear that the FDA recognizes that the decision to accept a surrogate endpoint for approval needs to be considered with a fuller understanding of our dataset," he added.

Sarepta is "encouraged" that the meeting minutes confirmed the FDA "had not made a final decision" regarding acceptability of the proposed accelerated approval filing and planned to review the requested data from Sarepta before rendering its verdict, he said.

The size of the eteplirsen and PMO safety database also were discussed at the end-of-Phase II meeting, and Garabedian said the company is continuing to collect long-term safety data from the ongoing eteplirsen extension study. Although Sarepta's Phase II study enrolled only 12 patients, Garabedian said the FDA noted in the meeting minutes that additional safety data to support approval could come from a pivotal confirmatory study – scheduled to begin in the first quarter of 2014 – should the agency agree to the accelerated approval filing.

Sarepta is preparing to submit the written dystrophin and clinical outcomes summaries and plans to seek a follow-up meeting with the FDA this quarter to discuss the additional data.

An end-of-Phase II CMC meeting with the agency likely will be delayed until the third quarter, but Garabedian stressed that eteplirsen's critical manufacturing and clinical development activities are on track to meet the timeline for an accelerated approval filing.

Pausing at the outset of Monday's call for a moment of silence in the aftermath of the bombs that shattered the nearby Boston Marathon, Garabedian apologized for the timing but said the company was committed to full disclosure about eteplirsen's regulatory path to approval.

Earlier this month, Sarepta reported updated data from Study 202, its Phase IIb open-label extension study of eteplirsen in DMD. Results at 74 weeks showed continued stabilization of walking ability in eteplirsen-treated patients evaluable on the six-minute walk test. Through 74 weeks, eteplirsen was well tolerated and there were no clinically significant treatment-related adverse events, serious adverse events, hospitalizations or discontinuations. Sarepta plans to include the 74-week dataset in the clinical outcomes summary provided to the FDA.

Study 202 met its primary endpoint of increased novel dystrophin as assessed by muscle biopsy at week 48. When initial results were disclosed in October 2012, the company's shares shot up 199.7 percent, hitting a 52-week high of $45. (See BioWorld Today, Oct. 4, 2012.)

At the time, Garabedian vowed the company would seek "the fastest path to approval."

In a company update following the call, Deutsche Bank analyst Robyn Karnauskas wrote that Sarepta acknowledged some surprise about the FDA's request for more data, adding that "we just don't know" if 74 weeks of data and "additional color on patients" will be enough to support an accelerated approval filing. Given the level of detail disclosed by Sarepta, however, expectations about eteplirsen's approval will be raised if the company goes that route, she said, maintaining a "buy" rating for the company.

But Leerink Swann LLC analyst Joseph Schwartz downgraded Sarepta to "market perform," citing potential loss of first mover advantage over exon-skipping candidate drisapersen (PRO051/GSK2402968) from Prosensa Therapeutics BV, of Leiden, the Netherlands, and partner GlaxoSmithKline plc, of London. In Phase IIb data, drisapersen showed a statistically significant benefit to DMD patients on the six-minute walk test, serving to de-risk upcoming Phase II U.S. and rest-of-world Phase III data, expected to report in the third and fourth quarters, respectively, according to Schwartz. (See BioWorld Today, Oct. 14, 2009, and Sept. 14, 2011.)