TY - JOUR
T1 - Biological impact of iberdomide in patients with active systemic lupus erythematosus
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.
N1 - Funding Information: This study was sponsored by Bristol Myers Squibb. Publisher Copyright: © 2022 BMJ Publishing Group. All rights reserved.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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.
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.
KW - B-Lymphocytes
KW - immune system diseases
KW - lupus Erythematosus, Systemic
UR - http://www.scopus.com/inward/record.url?scp=85130990850&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/annrheumdis-2022-222212
DO - https://doi.org/10.1136/annrheumdis-2022-222212
M3 - Article
C2 - 35477518
SN - 0003-4967
VL - 81
SP - 1136
EP - 1142
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 8
ER -