HYATTSVILLE, Md. -- Weighing hard data against patient testimonials, an FDA advisory panel voted 7-6 that a new Duchenne muscular dystrophy (DMD) failed to meet the minimum standards for accelerated approval on Monday.
The Peripheral and Central Nervous System Drugs Advisory Committee's vote signaled a lack of "substantial evidence from adequate and well-controlled studies" to trigger dystrophin production at a level considered "reasonably likely to predict clinical benefit."
In other words, the chosen surrogate endpoint was inadequate to promote any claim that the drug would actually help DMD patients -- at least in the majority's view.
The panel also voted 7-3, with three abstentions, that a single historically-controlled study also did not offer substantial evidence of the drug's efficacy.
In November, the same panel determined in more lopsided votes that the evidence in support of a similar agent, Biomarin's drisapersen, was also weak.
Benjamin Dupree, a 23-year-old with DMD from Dallas, who was the panel's patient representative, voted that the drug met the "substantial evidence" standard in the both questions.
However, the Duchenne patient was deeply conflicted. "The study doesn't provide what I think is adequate evidence to support all of this testimony that I'm seeing in here," he said, referring to extensive public testimony, before breaking down in tears.
Eteplirsen (tentatively branded Exondys 51), a product of Cambridge, Mass.-based Sarepta Therapeutics, has been proposed for treating DMD in patients with a specific verified mutation of the dystrophin gene. The disease is thought to occur when a genetic mutation in exon 51 causes a shortage or lack of dystrophin protein. Eteplirsen is intended to prevent exon 51 from being translated, enabling muscle cells to produce a shortened but still functional form of dystrophin.
The panel's first vote reflected the committee's views regarding the drug's suitability for approval under an accelerated approval pathway -- using dystrophin levels as a surrogate endpoint. The second vote viewed potential approval based on clinical efficacy.
, associate professor of psychiatry and behavioral sciences at John Hopkins University School of Medicine, voted against approval in either an accelerated or conventional approach.
While eteplirsen may have caused the production of some dystrophin, "it's very small ... too small to go from dystrophin production to clinical effect," he said.
Moreover, the question implies that dystrophin is responsible for clinical benefit, and "I'm not entirely sure that one should lock the clinical effect to the dystrophin production," he said.
Onyike, echoing Dupree, said, "What I would consider meaningful evidence of testimony from the families is not properly measured in the study."
director of the FDA's Office of Drug Evaluation I for the Division of Neurology Products, told the committee in opening remarks, "We come to you with sincere concerns, not because we take some perverse delight in keeping new medicines from those who urgently need them ... but because it is our -- we the FDA, and you, our advisory committee -- collectively, it is our fundamental responsibility to ensure, as required by law, that the treatments we approve are effective."
Dunn urged the panel to focus on "whether we can truly conclude that what these few eteplirsen patients are experiencing is clearly outside the natural variability of the disease."
During an unusually long public comment period, many parents pleaded with the committee to speed the drug's approval.
Mindy Leffler, from Seattle, described how her son regained the ability to pull himself into a car after taking eteplirsen. Leffler noted that "regaining definitively lost milestones" was not part of the natural progression for any Duchenne patient.
"Medical students are often told when they hear hoof-beats to think of horses not zebras," she urged the panel, "Look to the obvious conclusion, rather than searching for the unlikely. It is now time to stop hunting zebras."
When, at the end of a long day, Onyike called for an adequate controlled trial, as other panelists and FDA staff had before him, the audience erupted into jeers, shouting "biopsies hurt."
One wheelchair-bound teen, cursing angrily, ran his vehicle through a couple rows of empty chairs before rolling out of the room.
For this application, Sarepta submitted two exploratory studies and a single clinical trial in two phases -- a randomized placebo-controlled study and an open-label extension trial that used data from Italy and Belgium for comparison.
FDA's technical experts noted shortcomings in the sponsor's bioassay methods leading to possible "overestimation" of the percent of dystrophin-positive muscle fibers. The experts also pointed out the inability to distinguish drug-induced dystrophin from naturally-occurring dystrophin in immunofluorescence.
Sarepta's re-analysis of the biopsied tissue by three independent experts found a mean percent of dystrophin positive fibers of 17% [± 10%] at 180 weeks, which was about one-quarter to one-third of Sarepta's initial estimates at 48 weeks.
Similarly, using a Western blot assay, a fourth biopsy from patients at 180 weeks of treatment found dystrophin levels at 0.93% [± 0.84%] of normal muscle. The sub-1% increase was markedly different from the 10- to 20-fold increase with eteplirsen the sponsor initially reported at 12 weeks of treatment.
In the single clinical trial comparing three groups of four patients each at different doses -- eteplirsen 30 mg/kg or 50 mg/kg vs placebo, the drug failed its prespecified endpoints.
But the technical experts were more concerned with the way endpoints were defined. (For example two participants who completed the 10-meter walk-run (10MWR) also reported a score of zero on the 6-minute walk test (6MWT). This finding suggested possible subjectivity in decision-making regarding loss of ambulation.
The agency's technical experts also considered whether less capable or less motivated patients might more frequently be relegated to natural history studies, and whether this could have confounded study results.
Lastly, the sponsor's results showed no correlation between the amount of dystrophin patients had and their outcomes on the 6MWT.
Based on the clinical trial, the agency's experts ultimately concluded, "[T]here does not appear to be any evidence of efficacy for eteplirsen."
The FDA is not required to follow the advice of its advisory committees but it often does.