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

Clin Neuropharmacol. May-Jun 2005;28(3):126-32. doi: 10.1097/01.wnf.0000167360.27670.29.


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

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Alanine / administration & dosage
  • Alanine / adverse effects
  • Alanine / analogs & derivatives*
  • Alanine / pharmacology
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / blood*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Area Under Curve
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Azepines / administration & dosage
  • Azepines / adverse effects*
  • Azepines / pharmacology*
  • Dose-Response Relationship, Drug
  • Endopeptidases
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Half-Life
  • Humans
  • Male
  • Middle Aged
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / adverse effects*
  • Protease Inhibitors / pharmacology*
  • Single-Blind Method


  • Amyloid beta-Peptides
  • Azepines
  • N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide
  • Protease Inhibitors
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Alanine