S0815 Effect of Mirikizumab on Inflammatory Biomarkers in a Phase 2 Study of Patients with Crohn’s Disease

INTRODUCTION: Mirikizumab (miri; IL-23p19 antibody) is a humanized, IgG4 monoclonal antibody specifically targeting the p19 subunit of the IL23 cytokine. Prior studies have shown miri to have efficacy in psoriasis, ulcerative colitis, and Crohn’s disease (CD). High-sensitivity C-reactive protein (hsCRP) is a known marker of acute inflammation which correlates with disease activity in the majority patients, while fecal calprotectin (FCP) correlates with mucosal inflammation and can be used as a reliable biomarker of mucosal healing [1]. METHODS: At baseline, subjects (N = 191) were randomized with a 2:1:1:2 allocation across 4 treatment arms (PBO, 200, 600, 1000 mg miri, administered intravenously (IV) at Weeks 0, 4, 8). Fecal samples and serum were collected for the assessment of FCP and hsCRP, respectively, at baseline (BL) and Week 12. Comparisons to placebo for continuous data were done using the normal approximation for the Wilcoxon two-sample test. For categorical data, a logistic regression analysis was used with treatment, geographic region, and prior biologic CD therapy (prior biologic experience versus prior biologic naive) as factors. RESULTS: At Week 12, the percent change from BL in hsCRP was significantly greater in all miri groups compared to PBO ([median Q1, Q3] PBO: 43.8 [−8.3, 145.5]; 200 mg miri: −29.9 [−64.8, 25.9] P < 0.001; 600 mg miri: −39.8 [−70.6, 0.2] P < 0.001; 1000 mg miri: −48.6 [−76.1, 35.1] P < 0.001). The percent change from BL in FCP was significantly greater in the 600 and 1000mg miri groups compared to PBO (PBO: 0.0 [−60.9, 54.1]; 200 mg miri: −60.7 [−84.8, 68.0]; 600 mg miri: −62.1 [−84.4, −13.2] P < 0.05; 1000 mg miri: −76.2 [−90.7, −54.9] P < 0.001). The percentage of patients with normalized CRP (≤ 3 mg/L ) or FCP (≤ 250, 100, and 50 mg/kg) levels was significantly higher after miri treatment compared to PBO, with the highest proportion of patients in the 1000mg miri group (CRP: PBO 9.1%, 200 mg 4.3%, 600 mg 26.1% P < 0.01, 1000 mg 33.3% P < 0.05; FCP, 250 mg/kg cutoff: PBO 13.0%, 200 mg 28.6%, 600 mg 33.3% P < 0.01, 1000 mg 40.8% P < 0.05). CONCLUSION: The significant and dose dependent decrease of levels of hsCRP and FCP with miri treatment compared to PBO is consistent with results of clinical and endoscopic parameters and demonstrates the anti-inflammatory activity of miri. Notably, substantial proportions of patients had levels in a range observed in healthy subjects. [1] D'Haens, et al. Inflamm Bowel Dis. 2012; 18: 2218–2224.Table1