Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer’s disease

Springer Science and Business Media LLC - Tập 7 - Trang 1-7 - 2015
Rachelle S Doody1, Rema Raman2,3, Reisa A Sperling4, Eric Seimers5, Gopalan Sethuraman5, Richard Mohs5, Martin Farlow6, Takeshi Iwatsubo7, Bruno Vellas8, Xiaoying Sun9, Karin Ernstrom9, Ronald G Thomas3,10, Paul S Aisen3
1Alzheimer’s Disease and Memory Disorders center, Department of Neurology, Baylor College of Medicine, Houston, USA
2Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, Department of Neurosciences, University of California San Diego, La Jolla, USA
3Department of Neurosciences, University of California–San Diego, La Jolla, CA, USA;
4Department of Neurology, Harvard Medical School, Boston, USA
5Eli Lilly & Company, Lilly Corporate Center, Indianapolis, USA
6Department of Neurology, Indiana University, Indiana Alzheimer Disease Center, Indianapolis, USA
7Graduate School of Medicine, University of Tokyo, Tokyo, Japan
8Gerontopole UMR INSERM 1027, CHU, University of Toulouse, Toulouse, France
9Biostatistics Research Center, Department of Family and Preventive Medicine, University of California San Diego, La Jolla, USA
10Alzheimer’s Disease Cooperative Study, Department of Family and Preventive Medicine, Department of Neurosciences, University of California San Diego, La Jolla, USA

Tóm tắt

The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer’s disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures. The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman’s correlation coefficient. Assignment to the active treatment arms was associated with reduction in plasma amyloid-β (Aβ) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aβ peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aβ peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau. These findings may inform future studies of drugs targeting secretases involved in Aβ generation. ClinicalTrials.gov Identifier: NCT00594568 . Registered 11 January 2008.

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