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

Abstract

Background: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ 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. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).

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

Part 1 of the trial was designed to include a phase 2 lead-in safety cohort component. In the phase 2 lead-in safety period, patients were randomly assigned to one of three dose levels of verubecestat (12 mg, 40 mg, or 60 mg) or placebo. The first planned interim analysis, which was conducted 3 months after the first 200 patients underwent randomization, informed the decision to progress to phase 3. The data from these first 200 patients were excluded from the primary efficacy and safety analyses. Randomization continued during the 3 months after the 200th patient was enrolled, during which time approximately 200 additional patients were randomly assigned to a trial group, including 53 patients who were assigned to receive a 60-mg dose of verubecestat and whose data were excluded from the primary analyses. Scores on the Mini–Mental State Examination (MMSE) range from 0 to 30, with lower scores indicating poorer cognitive performance. MRI denotes magnetic resonance imaging.

Figure 2.. Mean Change from Baseline in the ADAS-cog and ADCS-ADL Scores over 78 Weeks (Part 1 of the Trial).

Panel A shows the mean change from baseline 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. Panel B shows the mean change from baseline 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. I bars indicate standard errors.