PO:11:303 Transcriptional changes associated with cenerimod therapy, a selective S1PR1 modulator, in systemic lupus erythematosus: results from the placebo controlled Phase 2b CARE trial

Objectives Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving dysregulated innate and adaptive immunity, with autoreactive B and T cells being central to its pathogenesis. Sphingosine-1-phosphate (S1P) regulates lymphocyte trafficking. In the phase 2b CARE study ( NCT03742037), the oral S1P receptor 1 (S1PR1) modulator cenerimod at the dose of 4 mg conferred greater improvements in modified (m)SLEDAI-2K (to exclude leukopenia) scores and, in alignment with its mode of action, greater reductions in lymphocyte proportions and SLE biomarkers compared to placebo. We assessed peripheral blood transcriptomic changes in SLE patients treated with cenerimod 2 mg (n=75), 4 mg (n=70), or placebo (n=77) over 6 months.Methods Peripheral blood samples were collected at baseline and month 6. RNA sequencing (Illumina) was used to quantify gene expression. Gene set enrichment analysis (GSEA) and cell type characterization (Cybersort, XCell2) were performed. Treatment response was defined by the SLE Responder Index 4 (SRI-4), requiring a greater than or equal to 4-point decrease in the mSLEDAI-2K no new BILAG-2004 A or greater than or equal to BILAG-2004 B, and no worsening in Physician’s Global Assessment by greater than or equal to 0.3 (scale 1–3).Results Baseline transcriptomic profiles showed activation of interferon-α/γ signaling, B/T-cell immunity, and inflammatory pathways. At month 6, cenerimod 2 and 4 mg led to greater suppression of these pathways than placebo, with stronger effects at 4 mg. Defense responses to infection remained unaffected. Both doses reduced circulating B and T cells, including naïve/memory B cells, CD4⁺/CD8⁺ T cells, and increased monocyte proportions. Neutrophil levels remained unchanged across groups. Cenerimod 4 mg downregulated interferon and T-cell signalling, ubiquitination, chromatin regulation, and cell cycle control to a greater extent in SRI-4 responders vs non-responders ( figure 1). Cenerimod 2 mg showed less pronounced effects; placebo showed minimal changes.Abstract PO:11:303 Figure 1Conclusions Transcriptional and cell subset analyses show that cenerimod modulates key pathogenic mechanisms such as interferon and T-cell signaling, while preserving host defense. These findings further support its therapeutic potential, currently evaluated in phase 3 trials (OPUS 1 and OPUS 2).