030 Etrasimod, an oral, selective sphingosine 1-phosphate receptor modulator improves skin inflammation in a contact hypersensitivity dermatitis model

Abstract

Etrasimod (APD334) is a selective sphingosine 1-phosphate receptor 1,4,5 (S1P1,4,5) modulator in development for atopic dermatitis (AD). S1P1 modulates trafficking of many immune cells, including those in eczematous skin. This study evaluated the effect of etrasimod on circulating and tissue immune cells and its impact on skin inflammation in a dermatitis mouse model. BALB/c mice were epicutaneously sensitized with fluorescein isothiocyanate (FITC) on the hind flank on Days (D) 0 and 5, then epicutaneously FITC challenged on the ear on D10-12. From D -1, mice were dosed orally once daily with vehicle, dexamethasone (Dex), or etrasimod (1 or 3 mg/kg). Ear thickness was measured with calipers on D0, 5, 10-13. On D2 and 13, draining lymph nodes (dLN) were analyzed by flow cytometry (FACS) for cellularity and activation. On D13, we examined blood for immune cell count and cytokines, and ear skin by FACS and histology. Sensitization did not cause skin inflammation, yet on D2 dendritic cells (DC), T cells and B cells expanded in the dLN in all mice. In vehicle mice, challenges amplified skin thickening from D10-13, and terminal analyses revealed worse histologic score and immune cell expansion in dLN and ear skin. Etrasimod dose-dependently lessened ear thickening and histologic score, with the high dose achieving comparable efficacy as Dex on D13. Etrasimod reduced lymphocyte frequency in the blood. In the dLN, etrasimod reduced DC influx, and decreased expansion and activation of T cells. B cells and eosinophils were also reduced in number. In the ear skin, the increase of T cells, B cells, and eosinophils was dose-dependently inhibited. In conclusion, etrasimod effectively reduced ear skin inflammation and dermatitis in FITC-induced hypersensitivity. Etrasimod significantly reduced the activation and expansion of immune cells after challenge in the dLN and ear skin. Notably, the dose-dependent reduction of immune cells in ear skin correlated with improvements in disease. This data encourages further study of etrasimod as a novel therapy for AD.