S928 Effect of Etrasimod on Circulating Lymphocytes in Patients With Moderately to Severely Active Ulcerative Colitis: Data From the Phase 3 ELEVATE UC 52 and ELEVATE UC 12 Trials

Abstract

Introduction: Etrasimod (ETR), is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator in development for the treatment of moderately to severely active ulcerative colitis (UC). Previous reports in healthy volunteers demonstrated selective effects of ETR on adaptive immune cell subsets with little effect on innate cells; however, the impact is unknown in patients with UC. Here, we report the effect of ETR on circulating immune cells in adults with moderately to severely active UC from the Phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials. Methods: In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), adults (16-80 years) with moderately to severely active UC and documented history of inadequate response, loss of response, or intolerance to ≥1 treatment for UC were randomized 2:1 to once-daily treatment with ETR 2 mg or placebo (PBO). In this exploratory analysis, whole blood was collected throughout the studies for characterization of immune cell subsets by flow cytometry. Mean (SE) percent change from baseline (in cells/μL) to Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 in ELEVATE UC 52 and Weeks 2, 4, 8, and 12 in ELEVATE UC 12 were compared between ETR 2 mg and PBO using 2-sided t tests. Results: Whole blood from 433 patients in ELEVATE UC 52 (ETR 2 mg, n=289; PBO, n=144) and 349 patients in ELEVATE UC 12 (ETR 2 mg, n=236; PBO, n=113) was included for immunophenotyping. Treatment with ETR 2 mg resulted in rapid mean (SE) percent reductions (in cells/μL) from baseline to Week 2, with nadir or near nadir changes from baseline reached by Week 4 in ELEVATE UC 52 and ELEVATE UC 12, respectively, for total T cells (CD3+: −55.6% [1.50] and −55.9% [1.65]), T helper cells (CD3+CD4+: −71.1% [1.33] and −72.5% [1.30]), cytotoxic T cells (CD3+CD8+: −35.7% [1.94] and −33.8% [2.60]), and B cells (CD3−CD19+: −74.5% [1.05] and −75.2% [1.18]); reductions were maintained through Week 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12. There were no notable changes in natural killer cells (CD3−CD56+CD16+) or monocytes (CD14+) during the treatment period of either study. Conclusion: Treatment with ETR has a rapid and differential effect on the frequency of circulating immune cell subsets in peripheral blood in patients with moderately to severely active UC. These findings may help explain the 5 serious infections in PBO and 3 in ETR observed in the ELEVATE UC 52 and ELEVATE UC 12 trials and the balanced overall infection rates across treatment arms in both studies.