An FDA advisory panel on Friday voted against approval of Biogen and Eisai's anti-amyloid antibody aducanumab, saying evidence from a single positive study is not enough to demonstrate the drug's efficacy in Alzheimer's disease in light of conflicting results from another trial. The panel vote follows the release of FDA briefing documents in which agency staff appeared to endorse the drug, stating that the companies had "provided substantial evidence of effectiveness to support approval."
The drugmakers are seeking approval of aducanumab, also known as BIIB037, to delay clinical decline in patients with Alzheimer's disease based on a controversial post-hoc evaluation of the Phase III EMERGE and ENGAGE trials.
The panel voted 8-1 that the positive EMERGE trial could not be viewed on its own as providing strong evidence supporting the effectiveness of aducanumab, without taking into account the conflicting ENGAGE data. Two other panelists were undecided on that question. The FDA also asked the advisory committee to consider post-hoc exploratory analyses that were conducted to help "achieve maximum understanding of the partially discordant results" of both trials, along with supportive data from a small Phase I trial dubbed Study 103, and evidence of aducanumab having a pharmacodynamic effect on Alzheimer's disease pathophysiology. Specifically, they were asked whether this could justify taking the EMERGE data as "primary evidence" to support the efficacy of aducanumab, with 10 panel members voting against and one vote cast as undecided.
The two identically-designed studies were discontinued last year after a failed futility analysis, but Biogen and Eisai later revived plans to seek US approval, claiming a new analysis showed high-dose aducanumab significantly slowed cognitive decline in the EMERGE study.
However, ENGAGE still showed no benefit, with Biogen attributing the conflicting results to mid-study protocol changes that had raised dosing and disproportionately benefited EMERGE participants. FDA reviewers appeared to agree, saying the ENGAGE study does not take away from the persuasiveness of EMERGE, although Tristan Massie, a statistician at the agency, did suggest that a third clinical trial should be conducted to clarify the benefit of aducanumab. "Excluding data from a large trial without sufficient justification is unscientific, statistically inappropriate and misleading," he told the advisory panel on Friday.
With regards further questions, seven panel members voted that Study 103 does not provide supportive evidence of the effectiveness of aducanumab, with four saying they were uncertain about the results. In addition, six panellists determined that Biogen had not "presented strong evidence" of a pharmacodynamic effect of aducanumab on Alzheimer's disease pathophysiology, while five panel members said the company had provided such evidence.
Billy Dunn, director of neurology products for the FDA's Center for Drug Evaluation and Research, said during the meeting that there is "a profound and enormous unmet medical need" for new Alzheimer's disease therapies. "Currently approved treatments do not target the underlying pathology of Alzheimer's disease and their beneficial effects are modest," he said
Meanwhile, panel member G. Caleb Alexander commented on the FDA's briefing materials, calling them "strikingly incongruent," while describing Massie's statistical review as "well done." Alexander said the agency did "an extraordinary amount of explaining around contrary findings," adding "it just feels like the audio and video on the TV are out of sync." However, Alexander noted "this is such an important application to get right because of the overwhelming imperative for new treatments."
The FDA is expected to make a final decision on Biogen and Eisai's drug by March 7 next year, with Jefferies analyst Michael Yee remarking the "FDA is gate-keeper and believes in the totality and safety is OK, so we think they could still approve." If aducanumab is cleared, Bloomberg analysts predict sales will total about $4.7 billion in 2025.
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