Responsiveness of systemic lupus erythematosus subjects to iberdomide based on molecular endotypes

• DOI: 10.1016/j.ard.2025.01.044
• Publication Date: 2025-02-27T12:23:44Z
• Authors: Prathyusha Bachali; Andrea Daamen; Shimon Korish; Yanhua Hu; Peter Schafer; Amrie Grammer; Peter E. Lipsky

Iberdomide is a cereblon E3-ligase modulator that promotes proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) was shown to be efficacious among subjects with generalised systemic lupus erythematosus (SLE). This study sought identify baseline gene expression profiles SLE responsive iberdomide analyse impact this agent on expression. Whole blood samples obtained from 276 female in phase 2b trial (NCT03161483) were assessed by RNA sequencing followed set variation analysis (GSVA) using 32 informative modules. Unsupervised K-means clustering categorised according molecular endotypes at baseline. Each endotype compared for treatment related changes. GSVA scores whole yielded 5 patient subsets (endotypes A-E) increases abnormalities indicative enhanced immune activity. Significant clinical responses iberdomide, determined Responder Index 4, confined C E. The most important modules responders E Treg cells, B interferon, whereas unfolded proteins, oxidative phosphorylation anergic/activated T cells associated responsiveness C. Molecular identified pharmacodynamic effects occurred all as well changes specific altered significant response. Thus, expression-based profiling may useful enrich trials treatment-responsive also monitor therapy.