Session Type: Poster Session (Tuesday)
Session Time: 9:00AM-11:00AM
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).
To cite this abstract in AMA style:Strasser D, Sippel V, Grieder U, Kieninger-Graefitsch A, Pierlot G, Farine H, Kulig P, Bourquin G, Keller M, Groenen P, Trendelenburg M, Murphy M. Cenerimod, a Potent, Selective and Orally Active Sphingosine 1-phosphate Receptor 1 Modulator, Reduced Blood Antibody-secreting Cells in Patients with SLE [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). 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/. Accessed December 10, 2019.
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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/