Biological impact of iberdomide in patients with active systemic lupus erythematosus

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 Stern, Sarah Hersey, Ying Ye, Allison Gaudy, Zhaohui Liu, Robert Gagnon, Shaojun Tang, Peter Schäfer · 发表于：Annals of the Rheumatic Diseases · 年份：2022 · DOI：10.1136/annrheumdis-2022-222212 · 被引用次数：37 · 研究领域：Systemic Lupus Erythematosus Research、Multiple Sclerosis Research Studies、Diabetes and associated disorders

Objectives 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). Methods 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. Results 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. Conclusion Iberdomide significantly reduced act...