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Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.
MedLine Citation:
PMID:  23288352     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
PURPOSE: 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:
Camilla Niva; Joanna Parkinson; Fredrik Olsson; Erno van Schaick; Johan Lundkvist; Sandra A G Visser
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-4
Journal Detail:
Title:  European journal of clinical pharmacology     Volume:  -     ISSN:  1432-1041     ISO Abbreviation:  Eur. J. Clin. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1256165     Medline TA:  Eur J Clin Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Neuroscience, CNSP Innovative Medicines, AstraZeneca, Södertälje, Sweden.
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