MIRIKIZUMAB-INDUCED TRANSCRIPTOME CHANGES in ULCERATIVE COLITIS PATIENT BIOPSIES at WEEK 12 ARE MAINTAINED THROUGH WEEK 52

Introduction:Mirikizumab, an anti-IL-23p19 monoclonal antibody, demonstrated efficacy in phase 2 and 3 randomized clinical trials of patients with moderate-To-severe ulcerative colitis (UC). Previous results have shown that 12 weeks of mirikizumab treatment down-regulated transcripts associated with UC disease activity and tumor necrosis factor inhibitor resistance. We assessed Week-52 gene expression from Week-12 responders receiving mirikizumab or placebo.Methods:In the phase 2 AMAC study (NCT02589665), mirikizumab-Treated patients achieving Week-12 clinical response were re-randomized to mirikizumab 200 mg subcutaneous every 4 or 12 weeks through Week 52 (N=31). Week-12 placebo responders continued placebo through Week 52 (N=7). The limma R package clustered transcript changes in colonic mucosa biopsies from baseline to Week 12 into differentially expressed genes (DEGs). Among DEGs, similarly expressed genes (DEGSEGs) maintaining Week-12 expression through Week 52 were identified.Results:Of 89 DEGSEGs, 63 (70.8%) were present only in mirikizumab induction responders, 5 (5.6%) in placebo responders, and 21 (23.6%) in both. Week-12 magnitudes and Week-52 consistency of transcript changes were greater in mirikizumab than in placebo responders (log2FC>1). DEGSEG clusters (from 84 DEGSEGs identified in mirikizumab and mirikizumab/placebo responders) correlated to modified Mayo score (26/84 with Pearson correlation coefficient [PCC]>0.5) and Robarts Histopathology Index (55/84 with PCC>0.5), sustained through Week 52.Discussion:Mirikizumab responders had broader, more sustained transcriptional changes of greater magnitudes at Week 52 versus placebo. Mirikizumab responder DEGSEGs suggest a distinct molecular healing pathway associated with mirikizumab IL-23 inhibition. The cluster's correlation with disease activity illustrates relationships between clinical, endoscopic, and molecular healing in UC.