Background/Purpose: Autoimmune diseases including SLE and SS are characterized by aberrant lymphocyte activation and autoantibody production. This results in systemic manifestations and the formation of tertiary lymphoid structures (TLS) leading to organ pathology, loss of organ function, and poor disease prognosis. SLE and SS are challenging to treat and are associated with mortality or severe disabilities.
Reported here are the proof-of-concept and efficacy of cenerimod, a potent, selective, and orally active sphingosine-1-phosphate receptor 1 (S1P₁) modulator, in mouse models of systemic (SLE) and organ-specific (SLE and SS) autoimmunity including TLS formation (SS).

Methods: SLE study: MRL/lpr mice were randomly assigned to either a cenerimod or vehicle group; the study was predefined to end when 20% mortality/morbidity was reached in one group. SS study: Salivary gland inflammation was induced in C57BL/6 (B6) mice by cannulation with replication-deficient adenovirus. B6 mice were therapeutically treated with either cenerimod or vehicle and sacrificed 15 days post cannulation. In both studies, target organs were evaluated for immune cell subsets, inflammatory cytokines, disease-relevant biomarkers, histopathology, and organ function.

Results: In the SLE study, all cenerimod-treated mice remained alive after 10 weeks of treatment, whereas >20% died in the vehicle group. Cenerimod-treated mice had significantly fewer circulating immune cells and immune cell infiltrates in kidneys, brain, and salivary glands. This translated to preserved organ function, with significantly reduced urine albumin concentration, kidney and brain histopathologic score, and local inflammatory milieu. Moreover, anti-dsDNA antibody and systemic BAFF and IFN-α levels were significantly reduced. In the SS study, cenerimod-treated mice displayed significantly reduced lymphocyte infiltration into salivary glands and abrogated expression of genes associated with TLS formation. Cenerimod induced TLS disaggregation and resolution of salivary gland inflammation with concomitant decreases in focus score, lymphoid structure size, and T/B-cell follicular organization, resulting in improved organ function with preserved saliva production.

Conclusion: Together, these data demonstrate that cenerimod treatment significantly ameliorated systemic and organ-specific autoimmunity, resulting in decreased inflammation and preserved organ function in animal models of SLE and SS. These results warrant investigation of cenerimod in autoimmune diseases characterized by systemic lymphocyte activation and organ damage. A phase 2b study evaluating the safety and efficacy of cenerimod in patients with SLE is currently recruiting (NCT03742037).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cenerimod-a-potent-and-selective-sphingosine-1-phosphate-receptor-1-modulator-controls-systemic-autoimmunity-and-organ-pathology-in-mouse-models-of-systemic-lupus-erythematosus-and-sjogrens/