PT  - JOURNAL ARTICLE
AU  - Lipsky, Peter E
AU  - Vollenhoven, Ronald van
AU  - Dörner, Thomas
AU  - Werth, Victoria P
AU  - Merrill, Joan T
AU  - Furie, Richard
AU  - Petronijevic, Milan
AU  - Velasco Zamora, Benito
AU  - Majdan, Maria
AU  - Irazoque-Palazuelos, Fedra
AU  - Terbrueggen, Robert
AU  - Delev, Nikolay
AU  - Weiswasser, Michael
AU  - Korish, Shimon
AU  - Stern, Mark
AU  - Hersey, Sarah
AU  - Ye, Ying
AU  - Gaudy, Allison
AU  - Liu, Zhaohui
AU  - Gagnon, Robert
AU  - Tang, Shaojun
AU  - Schafer, Peter H
TI  - Biological impact of iberdomide in patients with active systemic lupus erythematosus
AID  - 10.1136/annrheumdis-2022-222212
DP  - 2022 Aug 01
TA  - Annals of the Rheumatic Diseases
PG  - 1136--1142
VI  - 81
IP  - 8
4099  - http://ard.bmj.com/content/81/8/1136.short
4100  - http://ard.bmj.com/content/81/8/1136.full
SO  - Ann Rheum Dis2022 Aug 01; 81
AB  - 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 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.Trial registration number NCT03161483.The Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html