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

Abstract

Objectives: Iberdomide is a cereblon E3-ligase modulator that promotes proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) and was shown to be efficacious among subjects with generalised systemic lupus erythematosus (SLE). This study sought to identify baseline gene expression profiles of SLE subjects responsive to iberdomide and analyse the impact of this agent on gene expression.

Methods: Whole blood samples obtained from 276 female SLE subjects in the phase 2b iberdomide trial (NCT03161483) were assessed by RNA sequencing followed by gene set variation analysis (GSVA) using 32 informative gene modules. Unsupervised K-means clustering categorised subjects according to molecular endotypes at baseline. Each endotype was compared for treatment related gene expression changes.

Results: K-means clustering of GSVA scores from whole blood yielded 5 patient subsets (endotypes A-E) with increases in molecular abnormalities indicative of enhanced immune activity. Significant clinical responses to iberdomide, determined using the SLE Responder Index 4, were confined to endotypes C and E. The most important treatment related gene modules in responders in endotype E were Treg cells, B cells, and interferon, whereas unfolded proteins, oxidative phosphorylation and anergic/activated T cells were associated with responsiveness in endotype C.

Conclusions: Molecular profiles of SLE subjects identified pharmacodynamic effects of iberdomide that occurred in all endotypes as well as changes in specific gene modules altered in endotypes associated with a significant clinical response. Thus, gene expression-based molecular profiling may be useful to enrich clinical trials for treatment-responsive subjects and also monitor the pharmacodynamic impact of therapy.