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Amyloid β (Aβ) may play a central role in the pathogenesis of Alzheimer disease. A functional γ-secretase inhibitor, LY450139, was developed that inhibits Aβ formation in whole cell assays, transgenic mice, and beagle dogs. The authors wished to determine the safety and tolerability of this drug, and the reduction of Aβ in plasma and cerebrospinal fluid (CSF) after multiple doses. Volunteer subjects (N = 37) were studied using doses from 5 to 50 mg/day given for 14 days. Plasma and CSF concentrations of LY450139, Aβ1-40 and Aβ1-X (“Aβtotal”) were determined, and safety and tolerability were assessed. The plasma half-life of LY450139 was approximately 2.5 hours. Pharmacokinetic analyses showed a linear relationship between dose and plasma concentrations, with a Cmax of 828 ± 19.2 ng/mL after a 50-mg dose. Plasma Aβ concentrations decreased in a dose-dependent manner over a 6-hour interval following drug administration, with a maximum decrease of approximately 40% relative to baseline. After returning to baseline, Aβ concentrations were transiently increased. CSF Aβ concentrations were unchanged. Adverse events reported by subjects taking 5-mg, 20-mg, or 40-mg doses were similar to those reported by subjects taking placebo. Two of 7 subjects taking 50 mg/day experienced adverse events that may have been drug related. In this phase 1 volunteer study, reported adverse events after taking LY450139 were manageable. A dose-dependent reduction in plasma Aβ was demonstrated, and changes in plasma Aβ concentrations were temporally related to the pharmacokinetic characteristics of LY450139.