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A canine model to evaluate efficacy and safety of γ-secretase inhibitors and modulators


Year of Publication:
Contact PI Name:
Herman Borghys
Contact PI Affiliation:
Center of Excellence for Cardiovascular Safety and Mechanistic Pharmacology, Janssen Research and Development, Belgium
Marianne Tuefferd, Bianca Van Broeck, Ellen Clessens, Lieve Dillen, Willy Cools, Petra Vinken, Roel Straetemans, Filip De Ridder, Harrie Gijsen, Marc Mercken
Primary Reference (PubMED ID):
Funding Source:
Not Reported
Study Goal and Principal Findings:

Gamma-secretase, a membrane bound protease which cleaves the transmembrane protein amyloid- protein precursor (APP), is a therapeutic target for Alzheimer’s disease. Gamma-secretase inhibitors (GSIs) and modulators (GSMs) are being investigated as potential disease-modifying agents. Preclinical in vivo models to monitor the activity on gamma-secretase are described in different species such as mouse, rat, and guinea pigs. All these models have their value in testing compounds with amyloid lowering properties, however, compound characteristics and pharmacokinetic properties, as well as other species characteristics such as limited sampling volumes of cerebrospinal fluid (CSF), recommended the use of a larger, non-rodent animal species. For this purpose, a screening model in dogs was developed for testing GSIs and GSMs. This study showed that GSIs and GSMs had a dose- and time-dependent effect on Aβ37, Aβ38, Aβ40, and Aβ42 in CSF. Changes in liver function were evidenced by a transient increase in bilirubin with the GSMs and incidental increases in alanine aminotransferase for GSMs as well as GSIs. Microarray analysis of liver biopsies enabled to elucidate potential mechanisms behind the liver function changes. The relevance of the liver findings should be further evaluated in chronic pre-clinical safety studies and in humans. This study concludes that the dog is a very appropriate species to assess efficacy and safety of compounds which have an effect on APP processing such as GSMs, GSIs, and BACE-inhibitors. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
gamma Secretase
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
gamma Secretase
Therapy Type:
Small Molecule
Therapeutic Agent:
LY-450139 (Semagacestat)
Therapeutic Target:
gamma Secretase
Therapy Type:
Small Molecule
Therapeutic Agent:
BMS-708163 (Avagacestat)
Therapeutic Target:
gamma Secretase

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Applicable

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
CSF-beta Amyloid Peptide 38
CSF-beta Amyloid Peptide 40
CSF-beta Amyloid Peptide 42
CSF-beta Amyloid Peptide 40
CSF-beta Amyloid Peptide 42
Drug Concentration-Plasma
Drug Concentration-CSF
PK/PD Modeling
Blood t1/2
Area Under the Curve (AUC)
Target Engagement (Reduction beta Amyloid Peptides-Brain)
Blood/Serum Clinical Chemistry
Gene Expression Profile