Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease

Abstract

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.).

Copyright © 2019 Massachusetts Medical Society.

Figures

Figure 1.. Randomization, Trial-Group Assignment, and Follow-up in Part 1 of the Trial.

Only the most common reasons for exclusion from the trial are shown. Scores on the Repeatable Battery for the Assessment of Neuropsychological Status Delayed Memory Index (RBANS DMI) range from 40 to 160, with lower scores indicating worse memory. Scores on the Mini-Mental State Examination (MMSE) range from 0 to 30, with lower scores indicating poorer cognitive performance. PET denotes positron-emission tomography.

Figure 2.. Mean Change from Baseline in the CDR-SB, CCS-3D, and ADCS-ADLMCI Scores over 104 Weeks.

Panel A shows the mean change from baseline 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. Panel B shows the mean change from baseline in the score on the three-domain composite cognition score (CCS-3D; derived from the z scores [mean of 0, standard deviation of 1, with higher scores indicating worse cognition] of tests of episodic memory, executive function, and attention and processing speed). Panel C shows the mean change from baseline in the score on the Alzheimer’s Disease Cooperative Study Activities of Daily Living for Mild Cognitive Impairment Inventory scale (ADCS-ADLMCI); scores range from 0 to 53, with lower scores indicating worse function. Baseline is plotted at week −11, which is the mean assessment time of the baseline measurement as offset from the first dose of trial agent at week 0. As a result, there are no data plotted at week 0. The time course of the verubecestat groups between week −11 and week 0 was assumed to follow the same course as the placebo group. From this week 0 placebo coordinate, the time course for each respective verubecestat group was extended to the estimate at the first scheduled postdose time point. I bars indicate standard errors.