Biogen shocked the biopharma world last year when it resurrected its once-failed Alzheimer’s disease drug based on findings from a post hoc analysis. But its hopes for a speedy FDA nod look dashed as a panel of outside experts picked apart the data supporting the new drug application, panning it in multiple votes.
The Peripheral and Central Nervous System Drugs Advisory Committee voted 1-8, with two members voting “uncertain” that EMERGE, aka study 302—the phase 3 study on which aducanumab’s application hinges—provides “strong evidence that supports the effectiveness” of the drug as a treatment for Alzheimer’s.
And the drug fared no better in a second vote asking whether a small phase 1b study, called PRIME or study 103, provides “supportive evidence” for the efficacy of aducanumab; the tally came down 0-7, with four members voting “uncertain.”
The panelists took issue with the wording of the first voting question, where the FDA asked them to consider the data from study 302 “independently and without regard" for results from another study. That phase 3, called ENGAGE, or study 301, featured an “essentially identical design” to 302 but was deemed a failure.
“The studies were identical in design, identical in inclusion/exclusion criteria, identical—I presume—in biomarker analysis, so I have serious issues with how we can divorce the two studies from each other,” said Michael Gold, vice president of neurosciences development at AbbVie and the panel’s nonvoting industry representative.
“I don’t think the question was a reasonable request of us," said Caleb Alexander, M.D., a professor of epidemiology and medicine at Johns Hopkins University. “It doesn’t really seem fair, and I really can’t do 302 in isolation knowing about the existence of 301," he added.
And the panelists grappled with the 302 data themselves. Biogen early last year pulled the plug on both phase 3 studies after the program failed a futility analysis, but it later deemed that analysis was “incorrect.”
After a post hoc analysis, the company concluded that the 302 trial had succeeded, with patients on the highest dose of aducanumab logging a statistically significant improvement on a clinical dementia scale, but that 301 had failed, with patients on aducanumb doing worse than those taking placebo on that same measure.
But because of the original stoppage, multiple panelists felt the study was “truncated” or “not a full study.”
“There is a suggestion of an effect, but there are enough red flags in terms of the changes to the protocol, concerns about unblinding and the observation of efficacy in the final 78-week analysis without a full cohort of patients being able to contribute to that analysis, for me, doesn’t add up to a strong evidence,” said Aaron Kesselheim, M.D., an associate professor at Harvard Medical School.
And they weren't impressed with Biogen's other data, either. On the second voting question—whether the smaller 103 study provides supportive evidence of aducanumab’s efficacy—none of the panelists voted yes.
“Study 103 remains a phase 1b safety and tolerability study and should only be interpreted as such. It was not powered to measure clinical endpoints,” said Madhav Thambisetty, M.D., Ph.D., an adjunct professor of neurology at Johns Hopkins University and a senior investigator at the National Institutes of Health’s National Institute on Aging.
“In no way would I be accepting regarding this as an adequate, well-controlled trial,” said Scott Emerson, M.D., Ph.D., professor emeritus of biostatistics at the University of Washington, adding that he could have considered 302 as a pivotal trial, or 302 and 301 together as two confirmatory studies, but that 103 “cannot take the place of another confirmatory study.”
Even panelists who thought the phase 1b study showed signs of effectiveness agreed that it was not designed for that purpose. And Richard Perlmutter, M.D., of Washington University in St. Louis, cautioned against approving aducanumab simply because of desperation for new disease-modifying Alzheimer’s treatments.
“I think Alzheimer’s is a huge, urgent unmet need, but I also think that if we approve something where the data is not strong, we have a risk of delaying good therapies and effective therapies for more than a couple of years, for many years,” Perlmutter said. “There is a huge danger in approving something that turns out not to be effective."
Aducanumab did notch a small 5-0 win on the third voting question, which asked whether Biogen had “presented strong evidence of a pharmacodynamic effect on Alzheimer’s disease pathology.” The remaining six panelists voted “uncertain.” And the company came up empty on the final vote of the day, where the FDA asked whether the 302 study could stand alone as primary evidence of aducanumab’s efficacy. The panel voted 0-10 on that one, with one member voting “uncertain.”
An FDA rejection would be bad news for Biogen, which is facing problems on multiple fronts. For starters, its blockbuster spinal muscular atrophy drug Spinraza is staring down new competition from Roche's Evrysdi, while its multiple sclerosis med Tecfidera is under even more pressure from multiple generics. If the company's "highest priority" doesn't pan out, cost cuts could be down the line, executives said on a conference call in October.
Though the FDA is not bound to follow advisory committee recommendations, it often does. The agency is expected to decide aducanumab's fate by March 7.