Cenerimod, a selective S1P1 receptor modulator, has shown promising pharmacodynamic effects in a Phase 2b clinical trial (CARE) involving patients with moderate to severe systemic lupus erythematosus (SLE). The study, the results of which were published in Annals of the Rheumatic Diseases, evaluated the impact of cenerimod on interferon (IFN) signatures and other biomarkers associated with SLE. The results showed that a 4mg dose of cenerimod significantly reduced IFN-associated protein and gene signature biomarkers after 6 months compared with placebo.
The CARE trial (NCT03742037) investigated the effects of 2 mg and 4 mg doses of cenerimod compared to placebo in patients with SLE. Blood samples were collected at baseline and after 6 months of treatment to assess gene expression signatures for type 1 interferon (IFN-1), IFN-γ, and plasma cells. Cell-type deconvolution was performed to estimate cell abundance and evaluate dose-dependent pharmacodynamic effects.
Impact on Interferon Signatures
The study revealed that cenerimod 4 mg led to a notable reduction in IFN-associated protein and gene signature biomarkers after 6 months, relative to placebo. A more pronounced decrease in IFN proteins was observed in patients with high IFN-1 levels at baseline compared to those with low IFN-1 levels. Specifically, the median IFN-1 score in the IFN-1 high subgroup was reduced following 6 months of treatment with cenerimod 4 mg, and the transition from an IFN-1 low to high status was prevented, in comparison to placebo.
Dose-Dependent Effects
Cenerimod 4 mg demonstrated a larger effect size on key pharmacodynamic biomarkers, including IFN-1, IFN-γ, and plasma cells, when compared to the 2 mg dose. This suggests a dose-dependent response, with the higher dose potentially offering greater clinical benefits for patients with SLE.
Clinical Implications
These findings further elucidate the mechanism of action of cenerimod in SLE patients and provide a scientific basis for the ongoing Phase 3 clinical trials (OPUS-1 and OPUS-2) evaluating cenerimod 4 mg in moderate to severe SLE. The ability of cenerimod to modulate interferon signatures and prevent the transition to a high IFN-1 status may represent a significant advancement in the treatment of this complex autoimmune disease. 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.
