Introduction

Mirikizumab (miri) is a humanized, IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key mediator in the pathogenesis of IBD. We assessed the induction efficacy and safety of miri with a Phase 3, multi-center, randomized, parallel-arm, double-blind, placebo (PBO)-controlled trial (LUCENT 1; NCT03518086) in patients with moderate-to-severe ulcerative colitis (UC) who had inadequate or loss of response, or intolerance to corticosteroids, immunosuppressants, biologic therapies, or tofacitinib.

Methods

Adult patients (N=1281) were randomized in a 3:1 ratio to receive blinded intravenous administration of 300mg miri or PBO every 4weeks for 12weeks. Randomization was stratified by biologic failure status, baseline (BL) corticosteroid use, BL disease activity as measured by modified Mayo score, and world region. The primary objective was to test the hypothesis that miri was superior to PBO in inducing clinical remission at Week12. Key secondary objectives were clinical response, endoscopic and symptomatic remission, clinical response in biologic-failed patients, histologic-endoscopic mucosal improvement, and improvement in bowel urgency at Week12.

Results

BL characteristics were balanced across the 2 treatment groups. A significantly greater proportion of patients treated with miri achieved clinical remission at Week12 (Miri: 24.2%; PBO: 13.3%; Δ=11.1 [99.875%CI: 3.2, 19.1]; p=0.00006). Miri-treated patients achieved all key secondary endpoints, including a significantly greater average reduction in bowel urgency severity compared to PBO (p<0.00001). The frequencies of treatment-emergent adverse events (AEs) in miri-treated patients were similar to PBO. There were numerically fewer serious AEs (Miri: 27 [2.8%], PBO: 17 [5.3%]) and discontinuations due to AEs (Miri: 15 [1.6%], PBO: 23 [7.2%]) in miri-treated patients compared to PBO. There were 2 colon malignancies in the miri arm (0.2%) and no deaths during the treatment period.

Conclusions

In this Phase 3 UC study, 300mg miri IV demonstrated statistically significant and clinically meaningful improvements vs PBO in all primary and key secondary endpoints across clinical, endoscopic, histologic, and symptomatic measures, with an acceptable safety profile.

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