Safety, tolerability, and changes in amyloid β concentrations after administration of a γ-secretase inhibitor in volunteers

Amyloid beta (A beta) may play a central role in the pathogenesis of Alzheimer disease. A functional gamma-secretase inhibitor, LY450139, was developed that inhibits A beta 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 A beta 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, A beta(1-40) and A beta(1-x) ("A beta(total)") 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 C-max of 828 +/- 19.2 ng/mL after a 50-mg dose. Plasma A beta 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, A beta concentrations were transiently increased. CSF A beta 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 I volunteer study, reported adverse events after taking LY450139 were manageable. A dose-dependent reduction in plasma A beta was demonstrated, and changes in plasma A beta concentrations were temporally related to the pharmacokinetic characteristics of LY450139.