Biogen's and Eisai's shares both soared more than 40% on Wednesday after internal FDA staff documents released ahead of an advisory committee meeting set for November 6 suggested the companies had "provided substantial evidence of effectiveness to support approval" of aducanumab as a potential treatment for Alzheimer's disease. The drugmakers are seeking approval of the amyloid beta targeting antibody 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 two identically-designed studies were discontinued in March last year after a failed futility analysis. At the time, EMERGE, also known as study 302, was "trending positive," while ENGAGE, also known as study 301, was "unlikely to meet its primary endpoints" in patients with mild cognitive impairment or mild dementia. However, Biogen and Eisai later reversed course and revived plans to seek US approval, claiming a new analysis showed high-dose aducanumab significantly slowed cognitive decline in the EMERGE study, although there was still no benefit seen in ENGAGE.
On Wednesday, FDA staff agreed that the effect of aducanumab seen in EMERGE "is robust and exceptionally persuasive on several of the instruments used to evaluate efficacy." As a primary endpoint, both trials were assessing change from baseline Clinical Dementia Rating-Sum of Boxes (CDR-SB) score versus placebo in participants with early Alzheimer's disease, while secondary outcome measures included change from baseline in both the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog 13) subscale and in the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL-MCI) score.
Meanwhile, FDA reviewers noted that while the negative ENGAGE trial "does not contribute to the evidence of effectiveness of aducanumab," the results "do not meaningfully detract from the persuasiveness" of the EMERGE study. The agency staff added that there were no findings from exploratory analyses of the ENGAGE trial "that represented evidence that aducanumab is not effective."
However, the different results seen between the two trials in the post-hoc analysis have prompted some experts to recommend that a third Phase III trial be conducted to clarify aducanumab's benefit in Alzheimer's disease patients. That idea was echoed by reviewers at the FDA's Office of Biostatistics, who concluded that "the totality of the data does not seem to support the efficacy of the high dose," given that there was "only one positive study at best and a second study which directly conflicts with the positive study." They added that "another study is needed to confirm or deny the positive study and the negative study."
Biogen has attributed the difference between the EMERGE and ENGAGE trials to mid-study protocol changes that had raised dosing and disproportionately benefited EMERGE participants. In the staff documents released Wednesday, the FDA pointed out some possible factors, noting that among high-dose group patients in ENGAGE, clinical outcomes were "substantially impacted by an imbalance in a very small number of rapidly progressing participants." Participants in that trial also had lower exposures to the aducanumab target dose of 10 mg/kg. FDA reviewers said "it is reasonable to conclude that the partially discrepant results between [the two trials] are sufficiently well understood to allow independent consideration of…EMERGE."
Commenting on the news, Guggenheim analyst Yatin Suneja said the "briefing documents suggests a positive advisory committee vote, which bodes well for approval," while Salim Syed of Mizuho Securities called it "almost a best-case scenario" for Biogen. Further, Evercore analyst Umer Raffat remarked that although the data in the marketing application was not “high quality,” he still believed the drug was likely to be approved.
Meanwhile, analyst Paul Matteis of Stifel remarked "we are struck by...how consistent the agency's view of the data are with that of Biogen," but noted that the briefing documents include a "highly sceptical" in-depth statistical analysis of all of the trial data, an issue he said could crop up at the upcoming advisory meeting. He also pointed out that the meeting will include multiple committee members that have a history of negative votes.
The FDA is expected to make a final decision on Biogen and Eisai's drug by March 7 next year. If approved, analysts predict that aducanumab will generate sales of $5.3 billion by 2025.
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