Background/Purpose: Sphingosine-1-phosphate (S1P) regulates lymphocyte egress from lymphoid organs into circulation. In a SLE proof-of-concept study, cenerimod—a potent, selective S1P₁ receptor modulator—reduced circulating antibody-secreting cells and plasma IFN-associated biomarkers vs placebo (Strasser et al. rmdopen-2020-001261). Here, exploratory biomarkers associated with inflammation were evaluated in the phase 2b study (CARE) of cenerimod in moderate to severe SLE (NCT03742037).

Methods: Peripheral blood samples from patients with SLE participating in the phase 2b study (CARE) were collected at baseline and after 6 months of treatment with the S1P₁ receptor modulator cenerimod. Samples were collected in PAXgene tubes for gene expression analysis and EDTA plasma tubes for plasma protein expression. Gene expression was analyzed using the modular immune profile test (MIP) from DxTerity®. A high IFN-1 gene expression signature status (IFN-1 high) was identified using a 4-gene expression signature (IFIT1, HERC5, IFI27, RSAD2). Plasma proteins were measured using fit-for-purpose validated antibody-based assays.

Results: At baseline, patients with SLE were identified as either IFN-1 high or IFN-1 low. The distribution was well balanced in the placebo (n=86) and cenerimod 4 mg group (n=85) with approximately 50% IFN-1 high in both treatment arms. At baseline, the IFN-1 gene expression signature (GES) showed a bimodal distribution, and correlated with the IFN beta, IFN gamma, plasmablasts, and inflammation GES. The IFN-1 GES did not correlate with other adaptive and innate immune cell GES. None of the GES correlated with the mSLEDAI-2K at baseline. At 6 months, cenerimod treatment modulated GES and proteins linked to several of those molecular pathways associated with SLE pathogenesis.

Conclusion: At baseline, patients with SLE presented systemic molecular heterogeneity with clear separation of patients into IFN-1 high and IFN-1 low phenotypes. Of note, the IFN-1 phenotypes correlated with other inflammatory pathways, revealing a complex inflammatory pathogenesis in SLE. Cenerimod showed the potential to modify several of these inflammatory pathways demonstrating its broad immune-modulatory pharmacodynamics.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigation-of-pharmacodynamic-biomarkers-in-a-phase-2b-study-in-patients-with-moderate-to-severe-sle-treated-with-the-s1p1-receptor-modulator-cenerimod/