Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease

Arch Neurol. 2012 Nov;69(11):1430-40. doi: 10.1001/archneurol.2012.2194.


Objective: To assess the safety, tolerability, and pharmacokinetic and pharmacodynamic effects of the -secretase inhibitor avagacestat in patients with mild to moderate Alzheimer disease (AD).

Design: Randomized, double-blind, placebo-controlled,24-week phase 2 study.

Setting: Global, multicenter trial.

Patients: A total of 209 outpatients with mild to moderate AD were randomized into the double-blind treatment phase. The median age of the patients was 75 years,58.9% were APOE ε4 carriers, and baseline measures of disease severity were similar among groups.

Intervention: Avagacestat, 25, 50, 100, or 125 mg daily,or placebo administered orally daily.

Main outcome measures: Safety and tolerability of avagacestat.

Results: Discontinuation rates for the 25-mg and 50-mg doses of avagacestat were comparable with placebo but were higher in the 100-mg and 125-mg dose groups.Trends for worsening cognition, as measured by change from baseline Alzheimer Disease Assessment Scale cognitive subscale score, were observed in the 100-mg and125-mg dose groups. Treatment-emergent serious adverse events were similar across placebo and treatment groups. The most common reason for discontinuation was adverse events, predominantly gastrointestinal anddermatologic. Other adverse events occurring more frequentlyin patients undergoing treatment included reversibleglycosuria (without associated serum glucose changes), nonmelanoma skin cancer, and asymptomaticmagnetic resonance imaging findings. Exploratory cerebrospinal fluid amyloid isoforms and tau biomarker analysis demonstrated dose-dependent but not statistically significant reductions in a small subset of patients.

Conclusions: Avagacestat dosed at 25 and 50 mg daily was relatively well tolerated and had low discontinuation rates. The 100-mg and 125-mg dose arms were poorly tolerated with trends for cognitive worsening. Exploratory cerebrospinal fluid biomarker substudies provide preliminary support for -secretase target engagement,but additional studies are warranted to better characterize pharmacodynamic effects at the 25- and 50-mg doses.This study establishes an acceptable safety and tolerability dose range for future avagacestat studies in AD.

Trial registration: Identifier: NCT00810147

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activities of Daily Living
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / psychology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Body Weight / drug effects
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Enzyme Inhibitors / blood*
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Humans
  • Immunoprecipitation
  • International Cooperation
  • Magnetic Resonance Imaging
  • Male
  • Mass Spectrometry
  • Middle Aged
  • Neuropsychological Tests
  • Outcome Assessment, Health Care
  • Oxadiazoles / blood*
  • Oxadiazoles / therapeutic use*
  • Psychiatric Status Rating Scales
  • Sulfonamides / blood*
  • Sulfonamides / therapeutic use*
  • Time Factors
  • tau Proteins / cerebrospinal fluid


  • Amyloid beta-Peptides
  • BMS 708163
  • Enzyme Inhibitors
  • Oxadiazoles
  • Sulfonamides
  • tau Proteins
  • Amyloid Precursor Protein Secretases

Associated data