Background:SLE is an autoimmune disease characterized by aberrant lymphocyte activation and autoantibody production. In SLE, autoreactive lymphocytes migrate from lymphoid organs into the blood, and subsequently into tissue. This leads to systemic and multiorgan inflammation and pathology resulting in significant morbidity and mortality. Lymphocyte migration is a tightly controlled process driven by chemokine gradients. The chemotactic gradient across the vascular barrier established by sphingosine-1-phosphate (S1P) orchestrates egress of lymphocytes out of peripheral lymphoid organs into the blood. Cenerimod is a potent, selective, and orally active S1P receptor 1 (S1P1) receptor modulator that induces receptor internalization and thereby prevents lymphocyte egress from lymphoid organs into the blood [1].Objectives:In-depth preclinical and clinical characterization of cenerimod in modulating SLE.Methods:Lymphocytes from patients with SLE and healthy subjects were assessed for cenerimod-induced S1P1receptor internalization. Efficacy of cenerimod was evaluated in the MRL/lpr lupus mouse model. In a 12-week phase 2 clinical trial in patients with SLE treated with multiple doses of cenerimod (NCT02472795), lymphocyte subsets and inflammatory biomarkers were characterized.Results:Cenerimod was potent and efficacious at inducing S1P1receptor internalization in T and B lymphocytes with an EC50of 15 nM in both healthy subjects and patients with SLE. In lupus-like MRL/lpr mice treated with cenerimod, circulating T and B lymphocytes were reduced, which resulted in reduced immune infiltrates into tissue, reduced autoantibody production and inflammation, decreased proteinuria, and increased survival. In patients with SLE treated with cenerimod for 12 weeks, a dose-dependent reduction of circulating T cells (95%), B cells (90%), and antibody-secreting cells (85%) was evident. Furthermore, a reduction in anti-dsDNA antibodies and IFN-α, associated with an inflammatory phenotype, was observed.Conclusion:Cenerimod was potent and efficacious in reducing S1P1receptor surface expression on lymphocytesin vitro, and in reducing circulating T and B lymphocyte populations, including antibody-secreting cells, and in decreasing inflammatory biomarkers in patients with SLEin vivo. Furthermore, cenerimod significantly ameliorated systemic and organ-specific autoimmunity in a mouse model of SLE. These results support the further investigation of the clinical efficacy and safety of cenerimod in the ongoing phase 2b clinical trial (NCT03742037).References:[1]Piali L, Birker-Robaczewska M, Lescop C, Froidevaux S, Schmitz N, Morrison K, et al. Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties. Pharmacol Res Perspect. 2017 Dec; 5(6).Acknowledgments:This research was funded by Idorsia Pharmaceuticals LtdDisclosure of Interests:Daniel Strasser Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Estelle Gerossier Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Virginie Sippel Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Ursula Grieder Shareholder of: Idorsia options/shares, Employee of: Idorsia, Andrea Kieninger: None declared, Gabin Pierlot Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Hervé Farine Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Paulina Kulig Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Marcel Keller Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Sylvie Froidevaux Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Marten Trendelenburg Grant/research support from: Idorsia Pharmaceuticals Ltd, Novartis Institute of Biomedical Research, F. Hoffmann-La Roche Ltd, Marianne Martinic Shareholder of: Idorsia options/shares, Employee of: Idorsia employee, Mark Murphy Shareholder of: Idorsia shares and stock options, Employee of: Idorsia employee
SAT0165 PRECLINICAL AND CLINICAL CHARACTERIZATION OF CENERIMOD, A POTENT, SELECTIVE, AND ORALLY ACTIVE SPHINGOSINE-1-PHOSPHATE RECEPTOR 1 MODULATOR IN SLE