title: Evaluation of a candidate anti-arthritic drug using the mouse collagen antibody induced arthritis model and clinically relevant biomarkers.
abstract: The most rigorous scenario for testing a candidate rheumatoid arthritis therapeutic would be to use clinically relevant biomarkers and readouts to monitor disease development in an animal model that has a mechanism of disease that reflects the human condition. Treatment should begin when the full spectrum of arthritic processes, including bone damage, is present. We have tried to take this approach to evaluate a novel EP4 receptor antagonist (ER-886046) for its anti-arthritic potential. This work aimed not only to test a potential drug, but to also demonstrate a strategy for performing a more clinically relevant evaluation of future candidate arthritis treatments. A variety of biomarkers including: radiographic evaluation, clinical scoring, histology analysis, F4/80 macrophage immunohistochemistry, luminol bioluminescent imaging and (99m)Tc-MDP-SPECT imaging were evaluated as disease readouts in the mouse anti-collagen antibody induced arthritis model (CAIA). CAIA mice were treated either prophylactically or therapeutically with ER-886046 and the compound's efficacy was probed using the various biomarkers and compared to the reference drugs prednisolone and celecoxib. The various biomarkers effectively measured different aspects of arthritis pathology and consistently demonstrated the efficacy of ER-886046. The compound was found to be effective even when dosed therapeutically after bone damaging processes had initiated. The results presented herein demonstrate how biomarkers and a clinically relevant experimental design can be used to evaluate a candidate therapeutic. Utilization of clinically relevant biomarkers may provide a means for more translatable pre-clinical testing of candidate therapeutics and may provide information on their mechanism of action.
authors: Eisai Inc. 4 Corporate Drive Andover MA 01810, USA.
authors: Andrew T
authors: AT
authors: Bender
authors: Mark
authors: M
authors: Spyvee
authors: Takashi
authors: T
authors: Satoh
authors: Benjamin
authors: B
authors: Gershman
authors: Tyler
authors: T
authors: Teceno
authors: Laurette
authors: L
authors: Burgess
authors: Vipul
authors: V
authors: Kumar
authors: Yin
authors: Y
authors: Wu
authors: Hua
authors: H
authors: Yang
authors: Yueyun
authors: Y
authors: Ding
authors: Sandeep
authors: S
authors: Akare
authors: Qian
authors: Q
authors: Chen
keywords: Arthritis; EP4 receptor; PGE2; biomarkers; drug development; translational medicine
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