Background/Purpose: SLE is an autoimmune disease driven by autoreactive T and B lymphocytes. Lymphocytes infiltrate self-antigen expressing tissues, in which tertiary lymphoid structures are often observed, suggesting local generation of autoreactive effector cells. Autoreactive B lymphocytes produce autoantibodies leading to deposition of autoantibody immune complexes in tissues. The pathological process is amplified by secretion of inflammatory molecules. Reported here is the in-vitro and clinical characterization of cenerimod, a potent, selective, and orally active sphingosine 1-phosphate receptor 1 (S1P₁) receptor modulator (1).

Methods: All patients with SLE were classified according to ACR criteria. Primary lymphocytes from patients with SLE and healthy subjects were isolated from blood and characterized for S1P₁ receptor surface expression and cenerimod-induced S1P₁ receptor internalization by flow cytometry. In a phase 2 clinical trial in patients with SLE (NCT02472795) (2), blood T and B lymphocyte populations were enumerated by flow cytometry before and after 12-weeks of treatment with different doses of cenerimod. Unbiased analysis of flow cytometry data was employed to identify novel cenerimod-responsive lymphocyte populations. Inflammatory biomarkers were measured by ELISA in plasma samples.

Results: Surface expression of S1P₁ receptor was demonstrated on primary blood lymphocytes both in healthy subjects and patients with SLE in-vitro. S1P₁ receptor expression levels were ~3-fold higher on B cells compared to T cells. Cenerimod was potent and efficacious at S1P₁ receptor internalization in T and B lymphocyte populations with an EC₅₀ of ~15 nM in both healthy subjects and patients with SLE. In a cenerimod phase 2 clinical trial in patients with SLE, a dose-dependent reduction of blood T and B lymphocyte populations was evident, with a reduction of CD4+ T cells (up to 95%) and CD19+ B cells (up to 90%). Unbiased analysis discovered an ~85% cenerimod-induced reduction of blood antibody-secreting cells (CD45+/CD19+/CD27+/IgD-/CD20-/CD38++), which were demonstrated to be increased two-fold in patients with SLE compared to healthy subjects.

In the phase 2 clinical trial in patients with SLE, cenerimod reduced plasma IFN-a levels compared to placebo. IFN-a was shown to correlate with inflammatory molecules elevated in patients with SLE.

Conclusion: These data demonstrated for the first time S1P₁ receptor surface expression on blood T and B lymphocytes in patients with SLE, in which cenerimod was potent and efficacious in reducing S1P₁ receptor surface expression. In the phase 2 clinical trial in patients with SLE, cenerimod dose-dependently reduced blood T and B lymphocyte populations. Blood antibody-secreting cells, potentially involved in SLE pathogenesis, were increased in patients with SLE and reduced by cenerimod treatment in the phase 2 clinical trial.

The results warrant further investigation of the clinical efficacy of cenerimod and the impact on SLE biomarkers in the currently recruiting phase 2b clinical trial (NCT03742037).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cenerimod-a-potent-selective-and-orally-active-sphingosine-1-phosphate-receptor-1-modulator-reduced-blood-antibody-secreting-cells-in-patients-with-sle/