RT Journal Article
SR Electronic
T1 Biological impact of iberdomide in patients with active systemic lupus erythematosus
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1136
OP 1142
DO 10.1136/annrheumdis-2022-222212
VO 81
IS 8
A1 Lipsky, Peter E
A1 Vollenhoven, Ronald van
A1 Dörner, Thomas
A1 Werth, Victoria P
A1 Merrill, Joan T
A1 Furie, Richard
A1 Petronijevic, Milan
A1 Velasco Zamora, Benito
A1 Majdan, Maria
A1 Irazoque-Palazuelos, Fedra
A1 Terbrueggen, Robert
A1 Delev, Nikolay
A1 Weiswasser, Michael
A1 Korish, Shimon
A1 Stern, Mark
A1 Hersey, Sarah
A1 Ye, Ying
A1 Gaudy, Allison
A1 Liu, Zhaohui
A1 Gagnon, Robert
A1 Tang, Shaojun
A1 Schafer, Peter H
YR 2022
UL http://ard.bmj.com/content/81/8/1136.abstract
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