Verubecestat, Atabecestat Not Beneficial for Preventing Alzheimer Disease

WEDNESDAY, April 10, 2019 -- Use of the orally administered β-site amyloid precursor protein-cleaving enzyme 1 inhibitors, verubecestat and atabecestat, does not prevent clinical progression to Alzheimer disease, according to two studies published in the April 11 issue of the New England Journal of Medicine.

Michael F. Egan, M.D., from Merck in Kenilworth, New Jersey, and colleagues conducted a randomized, double-blind, placebo-controlled trial to examine verubecestat versus placebo for patients with memory impairment and elevated brain amyloid levels. After enrollment of 1,454 patients (485 to 12 mg/day verubecestat, 484 to 40 mg/day verubecestat, and 485 to placebo), the trial was terminated for futility. The researchers found that the estimated mean change from baseline to week 104 on the Clinical Dementia Rating Scale-Sum of Boxes was 1.65, 2.02, and 1.58, respectively, suggesting a worse outcome in the higher dose group.

David Henley, M.D., from Janssen Research and Development in Pennington, New Jersey, and colleagues conducted an interim analysis of the randomized placebo-controlled phase 2b/3 trial evaluating the efficacy and safety of atabecestat. A total of 557 participants were randomly assigned to either 5 mg atabecestat (189 participants), 25 mg atabecestat (183 participants), or placebo (185 participants). The researchers found that the least-squares means estimates of the change from baseline in the Preclinical Alzheimer's Cognitive Composite score at month six were −0.58 ± 0.22, −1.44 ± 0.22, and −0.32 ± 0.22 in the 5-mg, 25-mg, and placebo groups, respectively, favoring placebo over the higher dose.

"To be blunt, amyloid-beta lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer's disease forward," write the authors of an accompanying editorial.

The Egan study was funded by Merck, the manufacturer of verubecestat; the Henley study was funded by Janssen, the manufacturer of atabecestat.

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