title: Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men.
abstract: BACKGROUND
  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 Aβ concentrations in healthy male subjects. Secondary objectives included single-dose pharmacokinetics in CSF and plasma, safety and tolerability.
  
  
  METHODS
  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.
  
  
  RESULTS
  34 subjects were enrolled. Administration of a single dose of 200 or 400 mg of avagacestat resulted in a marked decrease in CSF Aβ(1-38), Aβ(1-40) and Aβ(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.
  
  
  CONCLUSIONS
  Avagacestat was safe, well tolerated, and resulted in a notable decrease in CSF Aβ concentrations, suggestive of γ-secretase inhibition. The results warrant further clinical study in patients with AD.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Hopewell, PO Box 5400, Princeton, NJ 08543, USA. gatong@gmail.com
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
authors.forename: Lorna
authors.initials: L
authors.lastname: Castaneda
authors.forename: Jun-Sheng
authors.initials: JS
authors.lastname: Wang
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Sverdlov
authors.forename: Shu-Pang
authors.initials: SP
authors.lastname: Huang
authors.forename: Randy
authors.initials: R
authors.lastname: Slemmon
authors.forename: Huidong
authors.initials: H
authors.lastname: Gu
authors.forename: Oi
authors.initials: O
authors.lastname: Wong
authors.forename: Hewei
authors.initials: H
authors.lastname: Li
authors.forename: Robert M
authors.initials: RM
authors.lastname: Berman
authors.forename: Christina
authors.initials: C
authors.lastname: Smith
authors.forename: Charles
authors.initials: C
authors.lastname: Albright
authors.forename: Randy C
authors.initials: RC
authors.lastname: Dockens
mesh_terms: D000284:Administration, Oral; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D019540:Area Under Curve; D015415:Biomarkers / Q000134:cerebrospinal fluid; D004311:Double-Blind Method; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D010069:Oxadiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics
chemical_list: D016229:Amyloid beta-Peptides; C554092:BMS 708163; D015415:Biomarkers; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010446:Peptide Fragments; D013449:Sulfonamides; C078639:amyloid beta-protein (1-38); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases