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Objectives: SLE is an autoimmune disease characterised by aberrant lymphocyte activation and autoantibody production. This study provides an in-depth preclinical and clinical characterisation of the treatment effect of cenerimod, a sphingosine-1-phosphate receptor type 1 (S1P 1 ) modulator, in SLE. Methods: Cenerimod effect on lymphocyte numbers, organ pathology, inflammation, and survival was evaluated in the MRL/lpr lupus mouse model. Lymphocytes from healthy subjects and patients with SLE were assessed for cenerimod-induced S1P 1 receptor internalisation. Lymphocyte subsets and inflammatory biomarkers were characterised in a 12-week phase 2 clinical study (NCT-02472795), where patients with SLE were treated with multiple doses of cenerimod or placebo. Results: In MRL/lpr mice treated with cenerimod, blood lymphocytes were reduced, leading to reduced immune infiltrates into tissue, and decreased tissue pathology, proteinuria, and inflammation, resulting in increased survival. Cenerimod was potent and efficacious in inducing S1P 1 receptor internalisation in lymphocytes in both healthy subjects and patients with SLE. In patients with SLE, 12-week cenerimod treatment resulted in a dose-dependent reduction of blood lymphocytes, antibody-secreting cells (ASC), and plasma IFN-α. Conclusion: Cenerimod significantly ameliorated systemic and organ-specific pathology and inflammation in a mouse model of SLE. In lymphocytes from patients with SLE, the S1P 1 receptor remained functional despite concomitant background medication. The preclinical lymphocyte reduction translated to patients with SLE and resulted in the normalisation of ASC and the reduction of IFN-associated biomarkers. The efficacy and safety of cenerimod is being further investigated in a long-term clinical study in patients with SLE (CARE; NCT-03742037).