The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis

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⁺CD45RB^high T-cell transfer mouse model of colitis.