title: Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  These findings may inform future studies of drugs targeting secretases involved in Aβ generation.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.
authors.affiliation: Alzheimer's Disease and Memory Disorders center, Department of Neurology, Baylor College of Medicine, 1977 Butler Blvd, Suite E5.101 Houston, TX USA.
authors.forename: Rachelle S
authors.initials: RS
authors.lastname: Doody
authors.affiliation: Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, M/C 0949, La Jolla, CA 92093 USA ; Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, M/C 0949, La Jolla, CA, 92093 USA.
authors.forename: Rema
authors.initials: R
authors.lastname: Raman
authors.affiliation: Department of Neurology, Harvard Medical School, 220 Longwood Avenue, Goldenson Building, Room 420, Boston, MA 02115 USA.
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
authors.affiliation: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285 USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Seimers
authors.affiliation: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285 USA.
authors.forename: Gopalan
authors.initials: G
authors.lastname: Sethuraman
authors.affiliation: Eli Lilly & Company, Lilly Corporate Center, Indianapolis, IN 46285 USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Mohs
authors.affiliation: Department of Neurology, Indiana University, Indiana Alzheimer Disease Center, 355 W. 16th Street, Suite 4700, Indianapolis, IN 46202 USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Farlow
authors.affiliation: Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8654 Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: Gerontopole UMR INSERM 1027, CHU, University of Toulouse, Toulouse, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.affiliation: Biostatistics Research Center, Department of Family and Preventive Medicine, University of California San Diego, 9500 Gilman Drive, M/C 0949, La Jolla, CA 92093 USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Biostatistics Research Center, Department of Family and Preventive Medicine, University of California San Diego, 9500 Gilman Drive, M/C 0949, La Jolla, CA 92093 USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Ernstrom
authors.affiliation: Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, M/C 0949, La Jolla, CA, 92093 USA ; Alzheimer's Disease Cooperative Study, Department of Family and Preventive Medicine, Department of Neurosciences, University of California San Diego, 9500 Gilman Drive M/C 0949, La Jolla, CA 92093 USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Thomas
authors.affiliation: Department of Neurosciences, University of California San Diego, 9500 Gilman Drive, M/C 0949, La Jolla, CA, 92093 USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen