Dataset Information

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

ABSTRACT: INTRODUCTION:The negative efficacy study examining the ?-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-? (A?) 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 A? 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 A? peptide but not AUC, supporting a link to inhibition of ?-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 A? generation. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.

SUBMITTER: Doody RS

PROVIDER: S-EPMC4461930 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Doody Rachelle S RS Raman Rema R Sperling Reisa A RA Seimers Eric E Sethuraman Gopalan G Mohs Richard R Farlow Martin M Iwatsubo Takeshi T Vellas Bruno B Sun Xiaoying X Ernstrom Karin K Thomas Ronald G RG Aisen Paul S PS

Alzheimer's research & therapy 20150610 1

<h4>Introduction</h4>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.<h4>Methods</h4>The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a plac ...[more]

PMID: 26064192

Similar Datasets

Project description:INTRODUCTION: Inhibition of gamma-secretase presents a direct target for lowering A? production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy. METHODS: In vitro assays monitoring inhibitor potencies at APP ?-site cleavage (equivalent to A?40), and Notch ?-site cleavage, in conjunction with a single cell assay to simultaneously monitor selectivity for inhibition of A? production vs. Notch signaling were developed to discover APP selective gamma-secretase inhibitors. In vivo efficacy for acute reduction of brain A? was determined in the PDAPP transgene model of AD, as well as in wild-type FVB strain mice. In vivo selectivity was determined following seven days x twice per day (b.i.d.) treatment with 15 mg/kg/dose to 1,000 mg/kg/dose ELN475516, and monitoring brain A? reduction vs. Notch signaling endpoints in periphery. RESULTS: The APP selective gamma-secretase inhibitors ELN318463 and ELN475516 reported here behave as classic gamma-secretase inhibitors, demonstrate 75- to 120-fold selectivity for inhibiting A? production compared with Notch signaling in cells, and displace an active site directed inhibitor at very high concentrations only in the presence of substrate. ELN318463 demonstrated discordant efficacy for reduction of brain A? in the PDAPP compared with wild-type FVB, not observed with ELN475516. Improved in vivo safety of ELN475516 was demonstrated in the 7d repeat dose study in wild-type mice, where a 33% reduction of brain A? was observed in mice terminated three hours post last dose at the lowest dose of inhibitor tested. No overt in-life or post-mortem indications of systemic toxicity, nor RNA and histological end-points indicative of toxicity attributable to inhibition of Notch signaling were observed at any dose tested. CONCLUSIONS: The discordant in vivo activity of ELN318463 suggests that the potency of gamma-secretase inhibitors in AD transgenic mice should be corroborated in wild-type mice. The discovery of ELN475516 demonstrates that it is possible to develop APP selective gamma-secretase inhibitors with potential for treatment for AD.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure