O1‐06‐05: First‐in‐human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta‐amyloid levels after single dosing

Abstract

Amyloid beta (Aβ) plaques are deposited in the brain in Alzheimer's disease (AD). Beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is a key enzyme responsible for the production of Aβ peptides. E2609 is a novel, small molecule, BACE1 inhibitor that has been shown in nonclinical studies to inhibit the production of Aβ40 and Aβ42 in brain, reducing Aβ in cerebrospinal fluid and plasma after oral dosing. We present results on the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of E2609 in a first-in-human study. This was a single-center, randomized, double-blind, placebo-controlled study in 8 cohorts of healthy adult subjects aged 30 to 55 and 1 cohort of healthy elderly subjects aged 65 to 85. Each cohort comprised 8 subjects, with 6 randomized to a single dose of E2609 and 2 to placebo. Healthy young subjects received single doses of 5, 10, 25, 50, 100, 200, 400 or 800 mg. Healthy elderly subjects received a single dose of 50 mg. Subjects were dosed after fasting overnight. Blood samples were collected predose and at multiple time points up to 144 h postdose to measure plasma concentrations of E2609 and Aβ peptides. Safety and tolerability were assessed by adverse events (AE), vital signs, electrocardiograms, and clinical laboratory blood tests. E2609 was well-tolerated across all doses. Twelve (21.8%) subjects treated with E2609 reported at least 1 AE, compared with 3 (16.7%) on placebo. E2609 exposure was approximately dose proportional, with a terminal elimination half-life of ∼15.9 h at 800 mg. E2609 showed prolonged inhibition of plasma Aβ1-xï€ at all doses from 5–800 mg (Figure 1). The maximum PD inhibition relative to baseline was 56.3% (at 5 mg) and 91.0% (at 800 mg) occurring approximately 6 to 24 hours postdose (Figure 2). At 72–144 h postdose (only sampled at 200–800 mg), plasmaAβ1-xlevels were still ∼25–45% below baseline, when E2609 was mostly eliminated. E2609 is a potent BACE1 inhibitor that causes prolonged reductions of plasma Aβ1-x after a single dose. There were no safety concerns with single doses up to 800 mg. Mean plasma concentrations of E2609 following single oral doses of E2609. Mean % change from Baseline in plasma Aβ(1-x) following single oral doses of E2609.