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Lymphocyte trafficking out of secondary lymphoid organs is regulated by concentration gradient–dependent interactions between the membrane-derived lysophospholipid signaling molecule sphingosine 1-phosphate (S1P) and the G-protein–coupled receptor, S1P1. Etrasimod is a novel, next-generation, small-molecule, oral S1P receptor modulator in clinical development for the treatment of immune-mediated inflammatory disorders, including ulcerative colitis. In preclinical pharmacology studies, etrasimod was a full agonist of recombinant human (6.1 nM EC50), mouse (3.65 nM EC50), dog (4.19 nM EC50), and monkey (8.7 nM EC50) S1P1 receptors, and a partial agonist of human S1P4 (147 nM EC50) and S1P5 (24.4 nM EC50), with relative efficacies of 63% and 73% of S1P response, respectively; whereas neither agonist nor antagonist activity was observed for human S1P2 or S1P3. A dose-dependent relationship was observed for etrasimod plasma concentration and lymphocyte count in mice, and chronic treatment with etrasimod resulted in attenuation of inflammation in a CD4+CD45RBhigh T-cell transfer mouse model of colitis.
Received October 9, 2018.
Accepted March 5, 2019.
This work was funded by Arena Pharmaceuticals, Inc. HA-S is an employee of Beacon Discovery Inc., which is the originating laboratory for the studies; KL-B is an employee of Beacon Discovery Inc.; CC is an employee of Beacon Discovery Inc.; MS reports; HKK is an employee of Arena Pharmaceuticals, Inc., the company that funded the studies; LP-B reports receiving honoraria from Merck, Abbvie, Janssen, Genentech, Ferring, Tillots, Vifor, Pharmacosmos, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer, Index Pharmaceuticals, Amgen, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestlé and Enterome; JA is an employee of Arena Pharmaceuticals, Inc.