P3‐415: E2012, a novel gamma‐secretase modulator, decreases plasma amyloid‐beta (Aβ) levels in humans

Abstract

The senile plaques of Alzheimer's Disease (AD) consist predominantly of two forms of Aβ, Aβ40 and Aβ42. A reduction of Aβ levels in the brain, in particular Aβ42, has been suggested as a therapeutic strategy for the treatment of AD. E2012 is a novel γ-secretase modulator shown in pre-clinical studies to inhibit the production of Aβ42 and Aβ40 without inhibiting the cleavage of Notch at pharmacologically active concentrations. Here we report the pharmacokinetic (PK) and pharmacodynamic (PD) results from a single ascending dose study with E2012 in humans. This was a randomized, double-blind, placebo-controlled study in healthy subjects (20-55 years old). Subjects received single oral doses of E2012 of 1, 2.5, 5, 10, 20, 50, 100, 200, 300 or 400 mg, or placebo. Plasma concentrations of E2012 and its active metabolite (ER381923) were measured by LC/MSMS and plasma levels of Aβ(x-40) and Aβ(x-42) were determined by ELISA. PK and PD parameters were calculated by non-compartmental methods. Single oral doses of E2012 reduced plasma levels of Aβ(x-40) and Aβ(x-42) in healthy subjects in a dose-related manner. As expected, Aβ(x-42) levels were decreased to a greater extent than Aβ(x-40) (maximum reductions at 400 mg of ∼50% and ∼30%, respectively), occurring 4-6 hrs post-dose without a rebound effect commonly observed with γ-secretase inhibitors. Average exposure (AUC0-∞) of E2012 and ER381923 increased in proportion to dose up to 400 mg. Mean maximum plasma concentration (Cmax) increased proportionally up to 200 mg and less than dose proportionally thereafter. Modeling of data obtained from rat studies with E2012 were predictive of the results obtained in humans for plasma Aβ effect over 24 hr. The effects on rat CSF and brain Aβ followed similar trends, supporting the use of CSF as a surrogate matrix to further evaluate E2012 effects on brain Aβ in humans. E2012, a novel γ-secretase modulator, differentially reduces plasma Aβ40 and Abβ42 levels in healthy human subjects following single dose oral administration. These results suggest that γ-secretase modulation may achieve substantial reductions in toxic Aβ species without the deleterious effects of Notch inhibition.