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The concentration of amyloid β (Aβ) peptides in cerebrospinal fluid (CSF) is a biomarker for Alzheimer's disease (AD) pathology, and has been used to evaluate the effectiveness of γ-secretase inhibition. Avagacestat is a selective γ-secretase inhibitor in development for the treatment of AD. The primary objective of this study was to assess the effects of single oral doses of avagacestat on the CSF concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability. This was a double-blind, placebo-controlled, randomized, single-dose study. Healthy male subjects were assigned to one of three sequential avagacestat dose panels (50, 200 and 400 mg) or placebo as single oral doses. 34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF (1-38), (1-40) and (1-42) concentrations vs placebo; with smaller decreases observed in the 50 mg dose group. Avagacestat was quickly absorbed into the systemic circulation, with a mean time to reach maximum plasma concentration (t(max)) of approximately 1-2 h, and a CSF t(max) of approximately 3 h. Adverse events were uncommon and occurred with similar frequency in the placebo and avagacestat groups. Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF concentrations, suggestive of γ-secretase inhibition. The results warrant further clinical study in patients with AD.


Gary Tong, Lorna Castaneda, Jun-Sheng Wang, Oleksandr Sverdlov, Shu-Pang Huang, Randy Slemmon, Huidong Gu, Oi Wong, Hewei Li, Robert M Berman, Christina Smith, Charles Albright, Randy C Dockens. Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men. Clinical drug investigation. 2012 Nov;32(11):761-9

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PMID: 23018285

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