BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the 
effect of drugs that modify the deposition of amyloid in the brain before the 
onset of dementia. Verubecestat is an orally administered β-site amyloid 
precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of 
amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial 
involving patients with mild-to-moderate dementia due to Alzheimer's disease.
METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week 
trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared 
with placebo, in patients who had memory impairment and elevated brain amyloid 
levels but whose condition did not meet the case definition of dementia. The 
primary outcome was the change from baseline to week 104 in the score on the 
Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, 
with higher scores indicating worse cognition and daily function). Secondary 
outcomes included other assessments of cognition and daily function.
RESULTS: The trial was terminated for futility after 1454 patients had been 
enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per 
day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day 
(the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 
patients, and 239 patients per group, respectively, completed 104 weeks of the 
trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB 
score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the 
placebo group (P = 0.67 for the comparison between the 12-mg group and the 
placebo group and P = 0.01 for the comparison between the 40-mg group and the 
placebo group), suggesting a worse outcome in the higher-dose group than in the 
placebo group. The estimated rate of progression to dementia due to Alzheimer's 
disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg 
group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 
mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for 
multiple comparisons), favoring placebo. Adverse events were more common in the 
verubecestat groups than in the placebo group.
CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among 
patients with prodromal Alzheimer's disease, and some measures suggested that 
cognition and daily function were worse among patients who received verubecestat 
than among those who received placebo. (Funded by Merck Sharp & Dohme; 
ClinicalTrials.gov number, NCT01953601.).