Etrasimod reduces adaptive immune cells in the periphery in UC

An exploratory analysis of the ELEVATE UC trials revealed that therapy with etrasimod has a rapid and differential effect on the frequency of circulating immune-cell subsets in the peripheral blood of patients with moderately to severely active ulcerative colitis (UC). Consistent with its proposed mechanism of action, etrasimod reduced T and B cells in the periphery, with a greater impact on CD4+ cells than on CD8+ cells.

Etrasimod is an investigational, once-daily, oral, selective sphingosine-1-phosphate (S1P) receptor modulator. Etrasimod partially and reversibly sequesters specific lymphocyte subsets in the lymph nodes, reducing circulating lymphocytes and resulting in fewer immune cells available to traffic to the GI tract [1]. However, the mechanism of action is unknown in patients with UC. The agent has already demonstrated efficacy in adults with moderately-to-severely active UC in the phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials [2,3]. In healthy volunteers, etrasimod has shown selective effects on adaptive immune cells, in particular CD4+ cells [4]. To further explore the effect of etrasimod on immune-cell subsets in UC, Prof. Silvio Danese (Vita-Salute San Raffaele University, Italy) performed a per-protocol, exploratory analysis of data from the ELEVATE UC 52 and ELEVATE UC 12 studies [5]. Whole blood was collected at weeks 2, 4, 8, and every 4 weeks up to week 52 in the ELEVATE UC 52 trial and at weeks 2, 4, 8, and 12 in the ELEVATE UC 12 trial for assessment of absolute lymphocyte counts and immunophenotyping.

Participants treated with etrasimod demonstrated nearly nadir (i.e. lowest point) absolute lymphocyte counts by week 2, which was maintained during the treatment period through week 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. In addition, treatment with etrasimod resulted in rapid mean percentage reduction from baseline to week 2, with nadir and near nadir changes reached by week 4 in both trials for total T cells, T-helper cells, cytotoxic T cells, and B cells. All reductions were maintained throughout the studies. In contrast, etrasimod did not influence natural-killer cells or monocytes in either study.

These results indicate that etrasimod has a rapid and differential effect on the frequency of circulating immune-cell subsets in the peripheral blood of patients with moderately-to-severely active UC, through sequestration of lymphocytes in the lymph nodes. Etrasimod reduced adaptive immune cells (T and B cells) in the periphery, with a greater impact on CD4+ cells than on CD8+ cells but spared innate immune cells that are important components of immune surveillance.

1. Al-Shamma H, et al. J Pharmacol Exp Ther. 2019;369(3):311–317.
2. Sandborn WJ, et al. Gastroenterology. 2020;158:550–61.
3. Sandborn WJ, et al. Abstract 968a, Digestive Disease Week 2022, 21–24 May, San Diego, USA.
4. Komori K, et al. Am J Gastroenterol 2020;115(Suppl 1):S12.
5. Danese S, et al. 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 UC12 trials. MP246, UEG Week 2022, 8–11 October, Vienna, Austria.

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Posted on 1 December 20228 April 2024