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DOP077 Immunomodulatory effects of etrasimod (APD334), an oral, potent, next-generation, selective S1P receptor modulator

Lee S.D.*1, Christopher R.2, Trokan L.2, Lassen C.2, Adams J.2, Chiorean M.3

1University of Washington Medical Center, Seattle, United States 2Arena Pharmaceuticals, Inc., San Diego, United States 3Virginia Mason, Digestive Disease Institute, Seattle, United States


Etrasimod is an oral potent, next-generation S1P modulator with an optimized S1P receptor activity profile that is currently in Phase 2 clinical development for ulcerative colitis.


Two randomised, double-blind studies evaluated safety, tolerability and pharmacodynamic (PD) responses of etrasimod, administered orally as single dose (dose-escalation design; 8 subjects/cohort) or repeat once daily (QD) dosing for 21 days (multiple ascending-dose design; 12 subjects/cohort), in healthy adults. PD parameters, including complete blood count (CBC) with differential, platelet count and lymphocyte immunophenotyping, were determined from peripheral blood sampling. Single-dose study assessments were Day −1, pre-dose (Day 1) and pre-specified times post-dose on Day 1, and up until Day 7 (Exit). Multiple-dose study assessments were screening, pre-dose (Day 1) and 4–8 hours post-dose on Days 1, 3, 5, 7, 9, 15, 21, 23 (Exit), and Day 28 (follow-up), with peripheral blood lymphocyte immunophenotyping performed on Days 1 and 21 (2mg cohort only).


In the single-dose study, etrasimod 3mg and 5mg induced a decline in absolute number of B cells, Natural Killer cells, and T cells (absolute and subsets): lower doses (0.1, 0.35 or 1mg) had little or no effect. In the multiple-dose study, lymphocyte lowering was dose-dependent, plateauing at 2mg: median reductions in lymphocyte counts were ∼67% with etrasimod 2 and 3mg, returning to baseline within 7 days of discontinuation. Reductions from baseline in T cells (as a % of white blood cell count [WBC] and lymphocytes) were greater with etrasimod (2mg) than placebo. The primary effect of etrasimod was seen in the Thelper and Tnaïve subpopulations, with a lesser extent in Tcentral memory cells (consistent with an expected retention of CCR7+ cells in secondary lymphoid tissue) [1]. Tsuppressor and Teffector memory cells were generally spared. Decreases in neutrophils were not consistently dose responsive: change from baseline in minimal neutrophil count (placebo subtracted) was 0.04–0.65×103/UL.


Etrasimod modulates lymphocyte subpopulations believed to be involved in IBD pathogenesis. These findings support further evaluation of this S1P modulator in clinical studies.


[1] Gergely P, et al. Br J Pharmacol 2012;167:1035–47.