Hypothesis
Removing aggregated amyloid beta with aducanumab would slow decline on the Clinical Dementia Rating Sum of Boxes in early Alzheimer's disease.
What failed
Both phase 3 trials were halted for futility on pooled interim data. In the fuller analyses, EMERGE met the primary endpoint (−0.39 for high dose vs placebo, P = .012) but ENGAGE did not (+0.03, P = .833), with 3,285 patients across 348 sites.
Broken assumption
Reducing amyloid burden translates into slower clinical decline — and does so consistently across identically designed trials.
Why
Biomarker substudies confirmed target engagement and dose-dependent reduction of Alzheimer's pathology markers in both trials, so the discordant clinical results came despite the drug doing what it was designed to do; amyloid-related imaging abnormalities with edema were the most common adverse event.
From the published paper: Haeberlein et al. The Journal of Prevention of Alzheimer s Disease, 2022. ↗CC BY