DUBLIN – The EMA has rejected Biogen Inc.’s application for European Union approval of Aduhelm (aducanumab), its controversial Alzheimer’s disease drug. Its human medicines committee (CHMP) issued a negative opinion on Biogen’s dossier during its December meeting this week, stating that the data from the key studies submitted in support of the application “were conflicting and did not show overall that Aduhelm was effective at treating adults with early stage Alzheimer’s disease.”

What’s more, CHMP noted, the amyloid beta-targeting antibody “could potentially cause harm,” as evidenced by abnormalities in brain scan images from some patients that may be evidence of bleeding or swelling. It also questioned whether these abnormalities could be “properly monitored and managed in clinical practice.”

The decision was reached on Dec. 16 but not publicly disclosed until Dec. 17. Cambridge, Mass.-based Biogen responded immediately by announcing it would seek a re-examination of the opinion. Once it has submitted the documentation setting out its grounds for the re-examination, the EMA will have 60 days to respond.

In the absence of any new clinical data, however, it will be difficult for Biogen to overturn the decision. Although patients remain desperately in need of therapies that are safe and effective, it is far from clear that Aduhelm ticks either box. The FDA approval of the drug in June triggered the resignations of three members of the advisory board that voted against 8–1 against (with two abstentions) in November 2020.

Additional evidence published since then raises further questions about its safety. According to a recent paper, published online on Nov. 22, 2021, in the Journal of the American Medical Association, 40% of participants in the Emerge and Engage phase III studies of Aduhelm exhibited amyloid-related imaging abnormalities, and about one-quarter of these patients experienced clinical symptoms, including headache, confusion, dizziness and nausea. Those numbers may be an underestimate, the study authors noted, due to the early termination of each study following negative futility analyses. Not all patients had completed a full course of therapy at that point – 35% of Emerge participants and 30% of Engage participants were deemed to have withdrawn from the studies.

Shares in Biogen (NASDAQ:BIIB) dropped by as much as 4.9% to a low of $224 during premarket trading but edged back to $231.81 by 8 am ET, off 1.6% from the previous close. But many investors remain bearish on the stock, following the backlash against the drug from payers and clinicians alike. The company’s stock closed at $395.85 in the wake of the FDA decision. It has been in more or less uninterrupted decline ever since.