Phase 2 Safety Trial Targeting Amyloid β Production With a γ-Secretase Inhibitor in Alzheimer Disease

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Abstract
LY450139 is a functional γ-secretase inhibitor that is currently under development as a disease-modifying therapy for Alzheimer disease (AD). As reported previously, LY450139 rapidly reduces amyloid β (Aβ) concentrations in the brain, cerebrospinal fluid (CSF), and plasma of transgenic V717F human amyloid precursor protein mice (PDAPP mice)1,2and in the plasma of humans.3In addition, the administration of LY450139 at doses of 30 mg/kg once daily for 5 months to PDAPP mice results in reduced accumulation of Aβ in the hippocampus and cortex, as measured by means of enzyme-linked immunosorbent assay.4Previous clinical studies using LY450139 with either healthy volunteers5or patients with AD6have shown short-term reductions in plasma Aβ40levels up to approximately 40% using single daily doses up to 50 mg. A single-dose escalation study3using 60, 100, or 140 mg in healthy volunteers demonstrated a dose-proportional increase in drug levels in plasma and CSF and a dose-dependent reduction in plasma Aβ levels.