Background: 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.
Methods: 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).
Results: 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) . 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.
Conclusions: Etrasimod modulates lymphocyte subpopulations believed to be involved in IBD pathogenesis. These findings support further evaluation of this S1P modulator in clinical studies.
 Gergely P, et al. Br J Pharmacol 2012;167:1035–47.