P045 Effect of Etrasimod on Circulating Lymphocyte Subsets: Data From a Randomized Phase 1 Study in Healthy Japanese and Caucasian Men.

Abstract

BACKGROUND: Etrasimod, a selective sphingosine 1-phosphate (S1P) receptor 1,4,5 modulator that reduces peripheral lymphocytes and subsequently impedes their recruitment to sites of inflammation, is in development for chronic immune-mediated inflammatory diseases. Reduction in pro-inflammatory immune cells without causing broad immunosuppression is an important treatment goal in patients with these diseases. This study evaluated the effect of etrasimod on circulating lymphocyte subsets in healthy volunteers to improve understanding of its proposed mechanism of action. METHODS: In this phase 1, single-blind (subject only) pharmacokinetic (PK) and pharmacodynamic study, 49 healthy Japanese and Caucasian men were randomized to receive once daily oral etrasimod 1 mg (n = 20), 2 mg (n = 20), or matching placebo (n = 9) from Days 1 to 7, followed by a 7-day washout and a single dose on Day 15. Absolute lymphocyte counts (ALC) were determined by complete blood count with differential. Immune cell subsets were evaluated by flow cytometry from isolated peripheral blood mononuclear cells (PBMCs) collected pre-dose on Days 1, 3, 5, 7, and 15. Change from baseline on 24 different immune cell subtypes were evaluated using a mixed-effects model. Paired t-tests were computed to evaluate significant subtype modulations in etrasimod-treated groups vs placebo at Day 7. RESULTS: Compared with placebo, etrasimod 1 and 2 mg dosed daily for 7 days resulted in similar dose dependent reductions in ALC in both ethnic groups, with total lymphocytes returning to at least 84% of baseline at Day 15. Compared with placebo, etrasimod induced reductions in mean percent change from baseline to Day 7 in total T cells, total CD4+ and CD8+ T cells, naive CD4+ and CD8+ T cells, central memory CD4+ and CD8+ T cells, effector memory CD4+ and CD8+ T cells, Th2 and Th17 cells, and total B cells. Etrasimod resulted in greater decreases in naive and central memory T cells than in effector memory T cells. Decreased immune cell subsets recovered to at least 70% of baseline pre-dose on Day 15, after the 7-day washout period. No notable treatment effects were seen on monocytes, macrophages, or CD56dim NK cells. Changes in immune cell populations were similar between Japanese and Caucasian subjects. Etrasimod 1 and 2 mg once-daily dosing regimens were safe and generally well tolerated. No adverse events related to low lymphocyte values occurred. CONCLUSION: Etrasimod effects on ALC and immune cell subsets were consistent with its known mechanism of action and observations for other S1P receptor modulators. Little or no ethnic group differences in etrasimod effects on ALC and immune cell subsets were observed in this study. The effect of etrasimod on onset and offset of immune modulation is consistent with etrasimod PK, with a typical half-life of approximately 33 hours. The differential effects of etrasimod on immune cell subsets may allow for a reduction in inflammation while maintaining immune surveillance. The lymphocyte subset profile suggests that etrasimod reduces certain immune cells and behaves as a selective immunomodulator rather than as a broad immunosuppressive agent.