Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease

BACKGROUND Alzheimer's disease is characterized by the deposition of amyloid-beta (A beta) plaques in the brain. A beta is produced from the sequential cleavage of amyloid precursor protein by beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by gamma-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the A beta level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P = 0.63 for the comparison between the 12-mg group and the placebo group and P = 0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was-8.4 in the 12-mg group,-8.2 in the 40-mg group, and-8.9 in the placebo group (P = 0.49 for the comparison between the 12-mg group and the placebo group and P = 0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events.