Pharmacodynamics of the S1P

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by autoreactive T and B lymphocytes. Sphingosine-1- phosphate (S1P) is involved in lymphocyte egress from peripheral lymphoid organs into the circulation. In phase 2a clinical trial, the potent, selective S1P1 receptor modulator cenerimod reduced circulating antibody-secreting cells and interferon (IFN)-associated biomarkers. Pharmacodynamic effects of 2 and 4 mg cenerimod were evaluated in the phase 2b clinical trial (CARE) in moderate to severe patients with SLE (NCT03742037). Blood samples were collected at baseline and after 6 months of treatment with cenerimod or placebo from CARE. The gene expression signatures for type 1 interferon (IFN-1), IFN-γ and plasma cells were used to assess dose-dependent pharmacodynamic effects of cenerimod. Cell-type deconvolution was performed to estimate cell abundance. Cenerimod 4 mg reduced IFN-associated protein and gene signature biomarkers after 6 months compared with placebo. A larger decrease of IFN proteins was evident in IFN-1 high patients compared with IFN-1 low patients. The median IFN-1 score in the IFN-1 high patients was reduced after 6 months of cenerimod 4 mg and the transition from IFN-1 low to high status compared with placebo was prevented. Cenerimod 4 mg exhibited a larger effect size on the pharmacodynamic biomarkers IFN-1, IFN-γ and plasma cells compared with cenerimod 2 mg. This study further characterised the mechanism of action of cenerimod in patients with SLE and substantiated the scientific rationale for cenerimod 4 mg in the phase 3 clinical trials in moderate to severe SLE (OPUS-1/-2).