Breaking the silence that has prevailed since last November on the upshot of ongoing talks with the FDA regarding eteplirsen, Sarepta Therapeutics Inc. said the FDA's once-dim view of data with the exon-skipping candidate for Duchenne muscular dystrophy (DMD) has changed.

A letter from the agency said the new drug application (NDA) "should be fileable" with existing data. Cambridge, Mass.-based Sarepta's shares (NASDAQ:SRPT) closed Monday at $33.980, up $9.58, or 39.3 percent, after trading as high as $44.60, as Wall Street reacted to the news that the company apparently will not need to conduct any new trials.

Pundits proved more cautious, however, citing other language in the FDA letter that noted the agency still has "significant concerns regarding [its] ability to draw valid conclusions" from the six minute walk test (6MWT) data and that it "remains skeptical about the persuasiveness of the (dystrophin) data" as a biomarker of efficacy. Leerink Partners LLC analyst Joseph Schwartz wrote in a research report that he "continue[s] to have reservations that the FDA will approve eteplirsen on its existing data set."

Sarepta said four meetings between November of last year and March 2014 resulted not only in a more favorable regard by the FDA of the existing data but also in clear guidance on an open-label, historically controlled confirmatory study of the compound.

Regulators also provided initial pointers on how the agency would regard a placebo-controlled study with follow-on DMD drug candidates which, like the open-label trial, could be considered an acceptable confirmatory experiment. Eteplirsen is designed for patients with DMD who have a genotype amenable to skipping of exon 51. Sarepta will submit investigational new drug applications for SRP-4053 and SRP-4045, which skip mutations in exons 53 and 45, in the third quarter of this year. Eteplirsen would be useful in only 13 percent of DMD patients, but Sarepta has seven other exon-skippers that could lead to treating about half of all patients.

Schwartz wrote that the FDA's "willingness to be patient and wait for more compelling/controlled data before approving eteplirsen" could be a double-edged sword, and suggests that the agency might continue doing so beyond the NDA filing. "Importantly," he noted, regulators do not like the idea of "excluding patients who lose ambulation while on drug from the analysis (modified intent-to-treat), which has been key for eteplirsen to compare favorably to historical control (which includes such patients)."

Eteplirsen itself has been hobbled by complications not strictly its own. Sarepta said last July, after an end-of-phase II meeting with the agency, that signs appeared good for an NDA filing in the first half of this year. In September, though, Leiden, the Netherlands-based Prosensa's drisapersen, partnered with Glaxosmithkline plc, of London, failed in a phase III trial – the likely cause of the FDA's changed outlook regarding the Sarepta compound. The primary endpoint in the drisapersen study was a statistically significant improvement on the 6MWT after 48 weeks. Although those in the drug treatment group (N = 125) attained a mean improvement of 10.33 meters over those in the placebo group (N = 61), the result was not statistically significant (p = 0.415). The 95 percent confidence interval spanned -15m to +35m. (See BioWorld Today, Oct. 14, 2009, April 17, 2013, July 25, 2013, and Sept. 23, 2013.)

FOURTH BIOPSY AHEAD?

After disclosing in November that the FDA said eteplirsen might need more trials though the "door was open" for officials to reconsider, Sarepta went quiet and discussions with regulators continued. In the most recent conference call, chatter focused less on what the FDA might end up requiring once all the cards are on the table and more on how the company will go about designing trials to come.

"They basically did not provide a hard time frame of follow up" for patients helped by eteplirsen, said CEO Chris Garabedian. "While we believe that we can show stability, like we showed in the phase IIb, as early as 48 weeks, I think the FDA is likely acknowledging that if we need to follow these open-label patients beyond 48 weeks, [then] that would be acceptable."

This structuring of clinical work so far "was with an understanding and expectation that this drug might be approved under the accelerated approval pathway, and therefore gives us a little more latitude in how long we can follow these patients to generate additional data," Garabedian added.

"We are anticipating that we may have staggered biopsies" to gauge efficacy, he said, possibly as many as four. "Patients would receive pre-treatment, but we may be looking at the time course of dystrophin over 24, 48 weeks. This is not part of the detailed guidance the FDA provided – this would be Sarepta's choice of what would be most meaningful and what would create the most compelling understanding and demonstration of the dystrophin production from eteplirsen."

Ed Kaye, Sarepta's chief medical officer, said assays already in place would be used and the FDA "would really just like confirmation of the dystrophin. They'll be working with the pathologists who have reviewed the data. They want to get comfortable with how it's done."

Garabedian was asked about the likelihood of DMD-afflicted boys' parents going along with four biopsies. "When this request came through last year, prior to November, we were challenged with getting support of the fourth biopsy," he acknowledged. "There wasn't a clear understanding of why this was important and how it was going to enable a higher likelihood of early access and approval of eteplirsen."

Now, the FDA has made clear that closer monitoring "could really support and enhance the dystrophin data set," Garabedian said. "We have not gone out to our investigator sites to reinitiate contact – obviously this is brand new news – but we intend to, and we hope that we get support from the boys in our study. If we were to capture that [fourth-biopsy data] later this year, we think we could turn that around and include it as part of an NDA filing."