title: Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.
abstract: OBJECTIVE
  To date, γ-secretase inhibition is the most frequently studied mechanism of reducing Aβ in clinical trials with as yet no therapeutic success for AD patients, as measured by the slowing down of cognitive decline or an improvement in cognitive function. The aims of this investigation were to evaluate whether the amyloid hypothesis has been tested clinically, and to explore whether preclinical data are predictive of clinical Aβ effects.
  
  
  METHODS
  A model-based-meta analysis on Aβ levels and drug exposure over time was performed on published and in-house (pre-)clinical data with γ-secretase inhibitors (GSIs; semagacestat, avagacestat, begacestat, PF-3074014, and MK0752).
  
  
  RESULTS
  The clinical data available did not show any significant or robust reduction of CNS Aβ over time at dose levels intended for AD patients. In contrast, these doses resulted in an average increase in plasma Aβ levels over a 24-h interval. A general agreement between preclinical and clinical data was found and allowed for interspecies extrapolations.
  
  
  CONCLUSIONS
  More substantially, CNS Aβ-lowering drugs are needed to test whether inhibition of Aβ production is efficacious in mild AD. Predictions based on preclinical data could assist in the selection of drug candidates and trial design.
authors.affiliation: Neuroscience, CNSP Innovative Medicines, AstraZeneca, Södertälje, Sweden.
authors.forename: Camilla
authors.initials: C
authors.lastname: Niva
authors.forename: Joanna
authors.initials: J
authors.lastname: Parkinson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Olsson
authors.forename: Erno
authors.initials: E
authors.lastname: van Schaick
authors.forename: Johan
authors.initials: J
authors.lastname: Lundkvist
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D013045:Species Specificity; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases