Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through...

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Mirikizumab, an anti-interleukin-23p19 antibody, has shown efficacy in moderate-to-severe ulcerative colitis (UC).
• Previous studies indicated mirikizumab downregulates UC-associated transcripts and those linked to TNF inhibitor resistance.

Purpose of the Study:

• To assess week-52 gene expression changes in patients with moderate-to-severe UC who responded to mirikizumab at week 12.
• To identify molecular pathways associated with mirikizumab treatment and their correlation with disease activity.

Main Methods:

• Analysis of colonic mucosa biopsies from the phase 2 AMAC study (NCT02589665).
• Gene expression profiling using the limma R package to identify differentially expressed genes (DEGs) and similarly expressed genes (DEGSEGs) from baseline to week 52.
• Correlation analysis of DEGSEG clusters with modified Mayo score and Robarts Histopathology Index.

Main Results:

• Mirikizumab responders exhibited broader and more sustained transcriptional changes compared to placebo responders.
• A significant proportion of DEGSEGs were unique to mirikizumab responders, suggesting a specific molecular healing signature.
• DEGSEG clusters correlated with clinical (modified Mayo score) and histopathological (Robarts Histopathology Index) measures of UC disease activity.

Conclusions:

• Mirikizumab treatment induces distinct and sustained molecular changes in UC patients, indicative of a healing pathway.
• These molecular changes are associated with clinical and endoscopic improvements, highlighting the role of IL-23 inhibition in UC.
• Gene expression profiling offers insights into the mechanisms of mirikizumab and can serve as a biomarker for treatment response.