Academic DMD Experts Criticize ‘Errors’ in FDA Ad Com Briefing Documents

More than 35 medical professors and experts have criticized the US Food and Drug Administration’s (FDA) review of a Duchenne Muscular Dystrophy (DMD) drug, citing errors in the agency’s advisory committee meeting briefing documents.

At issue is Sarepta’s drug eteplirsen, which the company is seeking approval as the world’s first treatment for DMD, a rare and fatal genetic disorder afflicting about 15,000 boys in the US. The drug was initially supposed to go before the Peripheral and Central Nervous System Drugs Advisory Committee in January, though that meeting was postponed because of snow until 25 April.

The initial release of the advisory committee documents in January was viewed by nearly every onlooker to be extremely negative, causing Sarepta’s stock to be cut in half, resulting in at least one investor lawsuit and pushing the company to file additional clarifications of “key inaccuracies in the FDA briefing document.”

In the statistical review section of the briefing documents, FDA officials said at the outset that the data on just 12 subjects “overall, did not provide statistical evidence to support the efficacy of eteplirsen.”

But now, according to DMD experts from UCLA, Stanford University, Harvard Medical School and other top medical schools, “errors” in some of the agency’s briefing documents “may lead to a false perception that there is little evidence that eteplirsen has any effect at slowing the progression of DMD.”

While recognizing that the company conducted a small study, creating “some uncertainty as to whether the findings will accurately represent subsequent observations in larger study groups,” the experts say that “the only way to address that uncertainty is to expose more individuals to the drug and assess efficacy on the overall amenable population over even longer periods of time. The excellent safety profile of eteplirsen makes this strategy reasonable.”

In addition, the academics are echoing what many of the mothers of the boys in the trial have been saying about their sons’ continued ability to walk.

“In these additional data (Sarepta Addendum), loss of ambulation data at 4 years of eteplirsen administration indicates that 4 of 4 (100%) boys on study 201/202 remained ambulant past the age of 14y, while only 2 of 10 (20%) in the Belgian/Italian external control group remained ambulant past age 14y,” the academics say. “Other available natural history data from United Dystrophinopathy Project, CINRG, and Duchenne Connect are consistent with the external control group supporting that on average only 20-30% of long-term steroid treated DMD patients remain ambulatory past age 14y.”

The academic experts also said the briefing documents contain “some scientifically questionable comparisons,” and that given “the relative paucity of patients with amenable mutations, the flexibility afforded by FDASIA [the Food and Drug Administration Safety and Innovation Act], 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."

The professors, who call on Billy Dunn, FDA’s director of the Division of Neurology Products, to pass along their comments to the advisory committee, also contend that “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. These three-year data alone are clearly supportive of accelerated approval, however the new 4-year data regarding age at loss of ambulation now provide even more compelling data for accelerated approval based on an irreversible morbidity.”

The drug’s PDUFA date has been extended by three months to 26 May to allow time for FDA to consider additional data including loss of ambulation and six-minute walk distance (6MWD) at four years, which were included in the Sarepta addendum.

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