医学
免疫学
红斑狼疮
系统性红斑狼疮
内科学
皮肤病科
重症监护医学
抗体
疾病
作者
Peter E. Lipsky,Ronald van Vollenhoven,Thomas Dörner,Victoria P. Werth,Joan T. Merrill,Richard Furie,Milan Petronijević,Benito Velasco Zamora,Maria Majdan,Fedra Irazoque-Palazuelos,Robert Terbrueggen,Nikolay Delev,Michael Weiswasser,Shimon Korish,Mark D. Stern,Sarah Hersey,Ying Ye,Allison Gaudy,Zhaohui Liu,Robert Gagnon,Shao-Jun Tang,Peter Schäfer
标识
DOI:10.1136/annrheumdis-2022-222212
摘要
Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE).Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling.Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (-58.3%), and plasmacytoid dendritic cells (-73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (-81.5%; p<0.001) but decreased other gene signatures in all patients.Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature.NCT03161483.
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