Duchenne docs--aka Sarepta investigators, advisers and advocates--back controversial case for eteplirsen

UCLA's Perry Shieh

Sarepta ($SRPT) enjoyed a rare spike in its share price today after several dozen experts in Duchenne muscular dystrophy, including a host of site investigators and advisers working on the drug, circulated a detailed letter explaining why the FDA should support the company's application for eteplirsen--despite a withering internal assessment from agency insiders.

On a point-by-point basis these physicians took exception to the FDA review, noting that despite the extremely small number of patients in the key study--with data on only 12 boys--their experience observing patients in their practices suggest that the drug was clearly effective. As news of the letter spread, Sarepta's share price surged 20%.

"The collective signatories note that the group of 12 eteplirsen treated boys, even accounting for daily deflazacort usage or twice-weekly prednisone, is clearly performing better than our collective clinical experience and the published literature would predict," the lineup of physicians asserts. "Collectively, a portion of us represent a group of physicians who have observed over 5,000 DMD patients in our practices over an average of more than 15 years. Published external natural history data and our clinical experience strongly support that the 12 boys treated for over 4 years show a milder clinical progression, likely due to a positive treatment effect of eteplirsen."

A quick check of Sarepta's websites and online records also revealed that many of the as-advertised experts have close ties to Sarepta, often listed as the very investigators who have been helping Sarepta gather the controversial data together and analyze it for regulators. Among those who have worked on drug trials related to eteplirsen and signed the letter are UCLA's Perry Shieh (a principal investigator for one study), Stanford's John Day (who lists Confirmatory Study of Eteplirsen in DMD Patients on his resume; and Kathy Mathews at the University of Iowa (a hub site investigator and principal). Harvard Med School's Louis Kunkel and the University of Washington's Jeff Chamberlain, who signed on to the company's advisory board, are also signers on the lobbying letter, along with many trial site leaders, including Anne Connolly, Susan Apkon, Nancy Kuntz and Basil Darras, all listed on Sarepta's website.

Dr. M. Carrie Miceli and Dr. Stanley Nelson, co-director of the Center for Muscular Dystrophy at UCLA, took the lead on the letter, which was dated February 24 and addressed to Dr. Billy Dunn, director of the division of neurology products at the FDA. The wife/husband team launched a public campaign advocating for new drugs to be approved for Duchenne, which afflicts their teenage son. Miceli, Nelson and Chamberlain also sit on the advisory board of CureDuchenne, an advocacy group which has offered its full-throated support of eteplirsen's approval, along with Sarepta CEO Ed Kaye.

In their view, which you can see here, the best approach would be to go ahead and approve eteplirsen and then go ahead and let upcoming data provide confirmatory results.

"The FDA Briefing Document also implies that the ongoing non-placebo controlled confirmatory eteplirsen trial (NCT02255552) and additional eteplirsen safety studies (NCT02420379 and NCT02286947) initiated in response to FDA guidance may not be considered sufficiently robust to allow for approval," the letter reads. "Given the relative paucity of patients with amenable mutations, the flexibility afforded by FDASIA, and the fact that many of the boys between the ages of 4 and 21 years with relevant mutations are already receiving eteplirsen in the context of these trials, it would be difficult to conduct a large placebo controlled study in the near future. Thus, it would be dubiously ethical to veer from the currently recommended study path at this point. In keeping with the criteria imposed by FDASIA for accelerated approval for rare disease with unmet need, we conclude that the aggregate data, described in the briefing documents, are providing substantial evidence of efficacy and use in the greater population of boys amenable to exon 51 skipping is appropriate. We suggest that the most scientifically robust way forward and the most ethical choice for the Duchenne community is in the context of an accelerated approval followed by a confirmatory trial."

Just how persuasive this group can be, with such close ties to Sarepta, won't be clear until April 25, when the FDA's advisory committee will finally meet for a review. The FDA's internal assessment virtually dismissed Sarepta's case. But the biotech has enjoyed intense support from parents and patients--as well as the professional community, which has played a big role in testing the drug.

Read more on