Abstract

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease driven by aberrant lymphocyte activation, autoantibody production, and inflammation, contributing to tissue damage. Cenerimod, a highly selective S1P1 receptor modulator, shows potential therapeutic effect in SLE through its immunomodulatory properties on lymphocyte trafficking, inflammation, and autoantigen transport [1]. In a Phase 2a clinical trial in patients with SLE, cenerimod reduced circulating antibody-secreting cells and plasma IFN-associated biomarkers vs placebo [2]. Objectives: Explore the pharmacodynamic effect of 2 and 4 mg cenerimod in the whole blood transcriptome in samples from the Phase 2b clinical trial (CARE - NCT03742037) in moderate to severe SLE. Methods: Peripheral blood samples from patients with SLE participating in CARE were collected at baseline and after 6 months of treatment with cenerimod. Samples were collected in PAXgene tubes for gene expression analysis. Gene expression was quantified by qPCR (DxTerity®) and total RNA sequencing (RNAseq). Cell type deconvolution was performed using the xCell method to estimate cell abundance and thus characterize the effect of cenerimod on blood cells. In addition, a priori defined gene expression signatures (summarized into z-scores) based on the cenerimod pharmacodynamics [2] (IFN-1, IFN-γ, and plasma cells) were used to assess the differences between the 2 and 4 mg cenerimod doses. Results: At baseline, the overall gene expression signatures and cell type abundances inferred by deconvolution were similar for the placebo, 2 and 4 mg cenerimod arms. A high correlation in IFN-1 gene expression values was observed with the two methods used for quantification, qPCR and RNAseq. IFN-1 gene signature score at baseline in individual patients correlated with gene signature score associated with plasma cells (R = 0.3, P = 0.003). After 6 months of treatment, cenerimod dose-dependently and significantly reduced IFN-1, IFN-γ, and plasma cell gene signatures (P < 0.001) in 4 mg cenerimod treated patients. Further, cenerimod dose-dependently reduced the estimated cell abundance of B and T cell subsets confirming previous observations. Specifically, a significant reduction when comparing cenerimod 2 and 4 mg at month 6 was observed in the following subsets: total memory CD4 T cells (P < 0.001), naïve CD8 T cells (P < 0.001) and central-memory CD8 T cells (P = 0.022) and plasma cells (P = 0.022). Conclusion: These results confirm the S1P1-dependent immunomodulatory properties of cenerimod and demonstrate that only 4 mg consistently reduced the investigated disease-relevant pathways. The efficacy and safety of 4 mg cenerimod is under evaluation in two Phase 3 clinical studies for SLE (OPUS – NCT05648500, NCT05672576). REFERENCES: [1] Hoyler et al. 2023 Lupus Science & Medicine. [2] Strasser et al. 2020 RMD Open. Acknowledgements: These studies are sponsored by Idorsia Pharmaceuticals Ltd. Medical writing support was provided by Anne Sayers (Idorsia Pharmaceuticals Ltd.) and funded by Idorsia Pharmaceuticals Ltd. We thank the patients for their participation and the investigators for their involvement in patient care and contribution to the study. Disclosure of Interests: Daniel Strasser Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Madeleine Suffiotti Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Pijus Brazauskas Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Aaron Hart Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Marianne Martinic Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Thomas Hoyler Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Gustavo Seifer Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Ouali Berkani Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Peter Cornelisse Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd, Mark Murphy Share options in Idorsia Pharmaceuticals Ltd, Employee of Idorsia Pharmaceuticals Ltd.