LO-016 The multifaceted immunomodulatory properties of cenerimod, a selective S1P1 receptor modulator, target three key aspects of SLE pathogenesis

Background Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by aberrant lymphocyte activation and autoantibodies. Formation and tissue deposition of immune complexes lead to auto-inflammatory reactions and release of further autoantigens, fueling a perpetual autoimmune process, ultimately leading to organ damage and tissue destruction.¹ Cenerimod, a highly selective S1P1 receptor modulator with a biased signaling, has the potential to target SLE pathogenesis due to its multifaceted immunomodulatory effects on lymphocytes, inflammation, and autoantigen transport.

Methods The impact of cenerimod on leukocyte distribution, autoantibody titers, inflammation, and antigen transport was assessed in a murine model of SLE and Sjögren’s Syndrome (MRL/lpr mice), in a proof-of-mechanism murine model for antigen transportation, and in two phase 2 clinical studies (NCT02472795 and NCT03742037), using flow cytometry, ELISA, and histology.

Results In MRL/lpr mice, therapeutic treatment with cenerimod significantly decreased tissue-infiltrating lymphocytes, autoantibodies, and inflammation, resulting in reduced kidney histopathological score, improved organ function, and increased survival.^{2 3} Furthermore, antigen transportation to draining lymph nodes was reduced. In a 12-week phase 2a clinical trial, treatment with cenerimod resulted in reduction of circulating T and B lymphocytes, antibody-secreting cells, autoantibodies, and IFN-α.^{2 4} These results were confirmed in a 12-month phase 2b clinical trial.⁵ which additionally showed that cenerimod 4 mg reduced pro-inflammatory cytokines and improved clinical disease activity (measured by SLEDAI-2K score modified to exclude leukopenia [mSLEDAI-2K] and SRI-4). Cenerimod is therefore hypothesized to act on three key aspects of SLE pathogenesis: autoreactive lymphocytes, general inflammation, and continuous autoimmune priming with new autoantigens (figure 1).

Conclusions Preclinical and clinical evidence suggests that cenerimod is a promising immunomodulatory drug candidate targeting several aspects of SLE pathogenesis. The ongoing confirmatory Phase 3 program OPUS (NCT05648500, NCT05672576) will further evaluate the safety and efficacy of 4 mg cenerimod in adults with SLE.

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References

1. Kaul A, et al. Systemic lupus erythematosus. Nat Rev Dis Primers 2016;2:16039.

2. Strasser DS, et al. Preclinical to clinical translation of cenerimod, a novel S1P1 receptor modulator, in systemic lupus erythematosus. RMD Open 2020;6(2):e001261.

3. Gerossier E, et al. Cenerimod, a selective S1P1 receptor modulator, improves organ-specific disease outcomes in animal models of Sjögren’s syndrome. Arthritis Res Ther 2021;23(1):289.

4. Hermann V, et al. First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomized, placebo-controlled, proof-of-concept study. Lupus Sci Med 2019;6(1):e000354.

5. Askanase A, et al. Efficacy and safety of cenerimod in patients with moderate to severe systemic lupus erythematosus (SLE): a multicenter, randomized, parallel-group, double-blind, placebo-controlled, dose-finding phase 2b trial. Arthritis Rheumatol 2022;74(suppl 9):3293–7.