Biogen’s hopes for a quick regulatory approval of its anti-Aβ antibody aducanumab may be dimming. An advisory panel convened by the U.S. Food and Drug Administration was unimpressed by the evidence for efficacy. In a seven-hour virtual meeting today, the panel of neurologists and biostatisticians picked apart Biogen’s case, pointing to discrepancies in the dataset. Not a single one of the 11-person panel considered the evidence sufficient for approval.
The application rested on the results from two Phase 3 trials, EMERGE and ENGAGE, which were halted after failing an interim futility analysis (Mar 2019 news). After analyzing additional data, Biogen shocked the field by announcing one of the two trials, EMERGE, was positive after all (Oct 2019 news). In post hoc analyses, Biogen researchers then argued that the failure of ENGAGE could be explained by a lower total exposure, due to a mid-trial dose increase. Even then, Alzheimer’s researchers had mixed reactions to this analysis (Dec 2019 news).
Biogen submitted its licensing application to the FDA four months ago; application to the European Medicines Agency is in the works (Jul 2020 news).
The biologics license application made the case that the EMERGE results were strong enough to form the basis for approval, and that the previous positive Phase 1b PRIME trial could serve as supporting evidence (Mar 2015 conference news; Sep 2016 news). Biogen and the FDA's neurologists both argued, essentially, that the negative ENGAGE trial did not detract from the positive EMERGE trial. This was the case, they said, not only because of the lower exposure to the 10 mg/kg high dose in ENGAGE, but also because a larger number of fast progressors in the high-dose ENGAGE group essentially drowned out an emerging treatment signal.
The panelists did not buy it. With one positive and one negative trial, the positive result is as likely to be the anomaly as the negative result, they noted. They even bemoaned an inherent bias in the briefing document toward aducanumab’s efficacy.
The panelists agreed that the evidence for aducanumab removing amyloid plaques was strong, and commended Biogen for pushing the program forward. At the same time, they questioned whether the data gathered thus far showed that this amyloid removal was meaningful for efficacy, noting a weak correlation between plaque clearance and the slowing of cognitive decline, and a paucity of biomarker and pathophysiology evidence downstream of plaque removal.
The panel praised the FDA’s biostatistical review of the aducanumab filing, which found numerous holes in the data. In contrast, the FDA’s internal neurology review favored approval. The panel expressed consternation at the profound disconnect between the two.
The FDA collaborated with Biogen in preparing this licensing application. In general, the panel welcomed such collaboration in the interest of finding better treatments for Alzheimer’s disease, but also expressed concern at how close the working relationship appears to have been in this case.
The agency is under pressure to approve aducanumab from some advocacy groups and patients, several of whom spoke movingly at the meeting. The Alzheimer’s Association issued a statement urging approval. In contrast, the global advocacy group Alzheimer Disease International put out a neutral statement about awaiting the panel’s decision “with bated breath.” A letter from the American Academy of Neurology urged careful consideration of the logistic and financial consequences of approving aducanumab now, but took no position on the data package itself.
The FDA usually follows the guidance from its advisory panels, but is not obligated to do so. A decision will come by March 2021.—Madolyn Bowman Rogers
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