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

Rachelle S. Doody, Rema Raman, Reisa A. Sperling, Eric Seimers, Gopalan Sethuraman, Richard Mohs, Martin Farlow, Takeshi Iwatsubo, Bruno Vellas, Xiaoying Sun, Karin Ernstrom, Ronald G. Thomas, Paul S. Aisen

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Introduction: 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. Methods: 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. Results: 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. Conclusion: These findings may inform future studies of drugs targeting secretases involved in Aβ generation. Trial registration: ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.

Original languageEnglish (US)
JournalAlzheimer's Research and Therapy
DOIs
StateAccepted/In press - Jun 10 2015

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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
Amyloid Precursor Protein Secretases
Alzheimer Disease
Pharmaceutical Preparations
Peptides
Area Under Curve
Placebos
Outcome Assessment (Health Care)
Drug Delivery Systems
Amyloid
Cerebrospinal Fluid
Analysis of Variance
Randomized Controlled Trials
Biomarkers
Safety
Inhibition (Psychology)
Therapeutics

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Cognitive Neuroscience

Cite this

Doody, R. S., Raman, R., Sperling, R. A., Seimers, E., Sethuraman, G., Mohs, R., ... Aisen, P. S. (Accepted/In press). Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease. Alzheimer's Research and Therapy. https://doi.org/10.1186/s13195-015-0121-6

Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease. / Doody, Rachelle S.; Raman, Rema; Sperling, Reisa A.; Seimers, Eric; Sethuraman, Gopalan; Mohs, Richard; Farlow, Martin; Iwatsubo, Takeshi; Vellas, Bruno; Sun, Xiaoying; Ernstrom, Karin; Thomas, Ronald G.; Aisen, Paul S.

In: Alzheimer's Research and Therapy, 10.06.2015.

Research output: Contribution to journalArticle

Doody, RS, Raman, R, Sperling, RA, Seimers, E, Sethuraman, G, Mohs, R, Farlow, M, Iwatsubo, T, Vellas, B, Sun, X, Ernstrom, K, Thomas, RG & Aisen, PS 2015, 'Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease', Alzheimer's Research and Therapy. https://doi.org/10.1186/s13195-015-0121-6
Doody, Rachelle S. ; Raman, Rema ; Sperling, Reisa A. ; Seimers, Eric ; Sethuraman, Gopalan ; Mohs, Richard ; Farlow, Martin ; Iwatsubo, Takeshi ; Vellas, Bruno ; Sun, Xiaoying ; Ernstrom, Karin ; Thomas, Ronald G. ; Aisen, Paul S. / Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease. In: Alzheimer's Research and Therapy. 2015.
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AU - Sethuraman, Gopalan

AU - Mohs, Richard

AU - Farlow, Martin

AU - Iwatsubo, Takeshi

AU - Vellas, Bruno

AU - Sun, Xiaoying

AU - Ernstrom, Karin

AU - Thomas, Ronald G.

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