Suffiotti Madeleine, Brazauskas Pijus, Keller Marcel Peter, Berkani Ouali, Seifer Gustavo, Cornelisse Peter, Murphy Mark Joseph, Strasser Daniel Stefan
Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Viatris, Allschwil, Switzerland.
Ann Rheum Dis. 2025 Feb;84(2):284-293. doi: 10.1136/ard-2024-226547. Epub 2025 Jan 16.
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 S1P 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).
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，其特征为自身反应性T和B淋巴细胞。鞘氨醇-1-磷酸（S1P）参与淋巴细胞从外周淋巴器官进入循环系统的过程。在2a期临床试验中，强效、选择性S1P受体调节剂西尼莫德减少了循环中的抗体分泌细胞以及与干扰素（IFN）相关的生物标志物。
在2b期临床试验（CARE）中评估2毫克和4毫克西尼莫德对中重度SLE患者（NCT03742037）的药效学作用。
在基线以及接受CARE研究中的西尼莫德或安慰剂治疗6个月后采集血样。使用1型干扰素（IFN-1）、IFN-γ和浆细胞的基因表达特征来评估西尼莫德的剂量依赖性药效学作用。进行细胞类型反卷积以估计细胞丰度。
与安慰剂相比，4毫克西尼莫德在治疗6个月后降低了IFN相关蛋白和基因特征生物标志物。与IFN-1低水平患者相比，IFN-1高水平患者中IFN蛋白的下降更为明显。4毫克西尼莫德治疗6个月后，IFN-1高水平患者的IFN-1评分中位数降低，与安慰剂相比，阻止了从IFN-1低水平向高水平状态的转变。与2毫克西尼莫德相比，4毫克西尼莫德对药效学生物标志物IFN-1、IFN-γ和浆细胞的效应大小更大。
本研究进一步明确了西尼莫德在SLE患者中的作用机制，并证实了4毫克西尼莫德在中重度SLE 3期临床试验（OPUS-1/-2）中的科学依据。
