Abstract

Background: In SLE, aberrant lymphocyte activation and autoantibody production result in deposition of immune complexes and contribute to tissue damage. Cenerimod, a highly selective S1P1 receptor modulator with a biased signaling, shows potential therapeutic effect in SLE through its immunomodulatory effects on lymphocyte trafficking, inflammation, and autoantigen transport. Preclinical and clinical data suggest that cenerimod may halt the vicious circle of autoimmunity, ultimately preventing organ damage in SLE. This abstract was presented at the 2023 ACR meeting.[1] Objectives: We combine results from preclinical and clinical studies to give a holistic view of the multifaceted immunomodulatory properties of cenerimod. Methods: A murine model of SLE (MRL/lpr mice) and a proof-of-mechanism murine model for antigen transportation were used to evaluate the effects of cenerimod on leukocyte distribution, autoantibody titers, inflammation, and antigen transport, using flow cytometry, ELISA, and histology.[2-4] Leukocytes, autoantibodies, and inflammation biomarkers were further assessed in two phase 2 clinical studies of once-daily cenerimod (0.5, 1, 2, or 4 mg) versus placebo in patients with SLE (NCT02472795 and NCT03742037 [CARE]).[4-6] In the first phase 2 study, patients were treated for 12 weeks. In the CARE study, treatment was for 12 months; patients assigned to cenerimod 4 mg were re-randomized to placebo or cenerimod 2 mg at Month 6. Results: In rodent disease models, cenerimod reduced the migration of dendritic cells to the draining lymph node, which was accompanied by reduced T cell proliferation and pro-inflammatory cytokine secretion. Furthermore, in the MRL/lpr lupus mouse model, treatment with cenerimod led to significant disease amelioration, evidenced by a reduction of tissue-infiltrating lymphocytes, lower titers of autoantibodies, and reduced levels of inflammatory cytokines. This was associated with reduced signs of pathology in the kidneys, improved kidney function, and increased survival. In the 12-week phase 2 clinical trial, treatment with cenerimod decreased circulating T and B lymphocytes, decreased autoantibody levels, and reduced secretion of pro-inflammatory IFN-α. These findings were supported in the CARE study, which showed that cenerimod 4 mg improved clinical indices of disease activity and reduced pro-inflammatory cytokines. Conclusion: Both preclinical and clinical research provide evidence that cenerimod is a promising immunomodulatory drug candidate that addresses three critical aspects of SLE pathogenesis: migration of autoreactive lymphocytes, release of pro-inflammatory cytokines and chemokines, and continuous autoimmune priming. The S1P1 receptor modulator cenerimod may effectively interrupt this pathogenic circle of SLE autoimmunity. The ongoing OPUS Phase 3 program (NCT05648500, NCT05672576) is designed to further investigate the safety and efficacy of cenerimod at a dose of 4 mg for the treatment of SLE in adults. REFERENCES: [1] Hoyler T et al. Arthritis Rheumatol 2023;75(Suppl. 9). Copyright © 2023 John Wiley & Sons Inc. Reproduced with permission of John Wiley & Sons Inc. [2] Hoyler T et al. Abstract LO-016. LUPUS KCR meeting 2023. [3] Gerossier E et al. Arthritis Res Ther 2021;23(1):289. [4] Strasser DS et al. RMD Open 2020;6(2):e001261. [5] Hermann V et al. Lupus Sci Med 2019;6(1):e000354. [6] Askanase A et al. Arthritis Rheumatol 2022;74(suppl 9):3293–7. 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: 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, Daniel Strasser 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.