Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase.

Objectives: gamma-Secretase inhibitors may be useful as disease-modifying drugs for the treatment of Alzheimer disease. LY450139 is a gamma-secretase inhibitor currently in clinical development, with doses being optimized through the use of biomarkers.

Methods: To further characterize biomarker responses to LY450139, single oral doses of 60, 100, or 140 mg were administered to volunteers without neuropsychiatric disease. Extensive safety assessments were obtained along with measures of changes in amyloid-beta (Abeta) in plasma and cerebrospinal fluid (CSF). A measure of the change in plasma Abeta1-40 was derived (area above the curve), which was determined by both the magnitude and duration of Abeta1-40 reduction.

Results: A total of 31 subjects (ages 49-53 years, 19 men) were enrolled. With the possible exception of headache, no clinically significant adverse events or laboratory changes were observed. A dose-proportional increase in drug exposure was present in plasma and in CSF. A dose-dependent change in plasma Abeta1-40 area above the curve was also demonstrated. Using the 140-mg dose, a maximum 72.6% reduction in plasma Abeta1-40 was demonstrated that did not return to baseline for more than 12 hours. Cerebrospinal fluid concentrations of Abeta were unchanged 4 hours after drug administration.

Conclusions: These data show that single doses of LY450139 up to 140 mg are accompanied by a dose-dependent plasma Abeta response. No response in CSF Abeta was apparent 4 hours after dosing.