title: Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (Avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers.
abstract: BACKGROUND
  γ-Secretase inhibitors (GSIs) are being investigated for their potential to modify the progression of Alzheimer disease based on their ability to regulate amyloid-β (Aβ) accumulation. BMS-708163 (avagacestat) is an oral GSI designed for selective inhibition of Aβ synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Aβ synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class. Avagacestat produced up to 190-fold greater selectivity for Aβ synthesis than Notch processing in preclinical studies and may therefore produce less toxic adverse events than other less selective compounds. Presented here are the results of the first in-human study for this new GSI compound.
  
  
  OBJECTIVE
  The goal of this study was to assess the tolerability profile, pharmacokinetic properties, and effects on pharmacodynamic markers (Aβ, trefoil factor family 3 protein, dual specificity phosphatase 6, and hairy and enhancer of split-1) of single, oral doses of avagacestat in healthy, young, male volunteers.
  
  
  METHODS
  This was a multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study in 8 healthy young men (age, 18-45 years) per dosing panel. Each study participant was randomized to receive a single dose of placebo (n = 2) or avagacestat (n = 6 for each dose) as an oral solution in 1 of 9 sequential dose panels (0.3, 1.5, 5, 15, 50, 100, 200, 400, and 800 mg). For determination of avagacestat, blood samples were obtained before dosing and for up to 144 hours after dosing. For participants in the 800-mg avagacestat dose panel, additional samples were obtained at 216, 312, and 648 hours. For 40-amino acid isoform of Aβ (Aβ(1-40)) assessment, plasma samples were collected before avagacestat administration and up to 72 hours after dosing.
  
  
  RESULTS
  Avagacestat concentrations peaked quickly after oral administration and then had a biphasic decrease in concentrations with a prolonged terminal phase. Exposures were proportional with doses up to 200 mg. Avagacestat was well tolerated at single oral doses up to 800 mg, with a biphasic effect on plasma Aβ(1-40). Adverse events were predominately mild to moderate in severity with no evidence of dose dependence up to 200 mg.
  
  
  CONCLUSIONS
  Results from this single-ascending dose study suggest that avagacestat was tolerated at a single-dose range of 0.3 to 800 mg and suitable for further clinical development.
authors.affiliation: Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA. Gary.Tong@bms.com
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
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: Robert
authors.initials: R
authors.lastname: Croop
authors.forename: Lorna
authors.initials: L
authors.lastname: Castaneda
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 F
authors.initials: CF
authors.lastname: Albright
authors.forename: Randy C
authors.initials: RC
authors.lastname: Dockens
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000097:blood; D051792:Basic Helix-Loop-Helix Proteins / Q000097:blood; D015415:Biomarkers / Q000032:analysis*; D004305:Dose-Response Relationship, Drug; D054642:Dual Specificity Phosphatase 6 / Q000097:blood; D018398:Homeodomain Proteins / Q000097:blood; D006801:Humans; D008297:Male; D010069:Oxadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000097:blood; D010455:Peptides / Q000097:blood; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000072056:Transcription Factor HES-1; D000071165:Trefoil Factor-3; D055815:Young Adult
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D054642:Dual Specificity Phosphatase 6; D018398:Homeodomain Proteins; D010069:Oxadiazoles; D010446:Peptide Fragments; D010455:Peptides; D013449:Sulfonamides; D000072056:Transcription Factor HES-1; D000071165:Trefoil Factor-3; C554092:BMS 708163; C082495:TFF3 protein, human; C078592:amyloid beta-protein (1-40); C078493:HES1 protein, human; C517035:DUSP6 protein, human