DOP52 Reduction in inflammatory biomarkers in a Phase 2 study of mirikizumab in patients with moderately to severely active ulcerative colitis. (25th January 2019) - Sandborn, W J
Abstract: Background: Interleukin (IL)-23 is a cytokine involved in the pathogenesis of ulcerative colitis (UC). Mirikizumab (miri) is a p19-directed IL-23 antibody that demonstrated efficacy and was well-tolerated following 12 weeks of induction treatment in a Phase 2 randomised clinical trial (AMAC, NCT02589665). 1 Exploration of IL-23 pathway biomarkers supports an understanding of drug activity and mechanism of action. This abstract describes exploratory biomarker results for IL-23 pathway cytokines IL-22 and IL-17A, and their associations with clinical outcomes in this study. Methods: Patients with moderately to severely active UC (Mayo score 6–12 with a minimum endoscopic subscore [ES] ≥2) were randomised 1:1:1:1 to receive intravenous (IV) placebo (pbo) ( N = 63), miri 50 mg ( N = 63) or 200 mg ( N = 62) with possibility of exposure-based (EB) increases, or fixed miri 600 mg ( N = 61) every 4 weeks, with efficacy assessment at Week 12. Plasma EDTA samples were collected at Weeks 0, 4, and 12 to evaluate circulating levels of IL-17A and IL-22. The ultrasensitive Quanterix Simoa platform (IL-17A) and a custom Meso Scale Discovery assay (IL-22) were used to evaluate cytokine levels. Biomarker results were analysed using a Mixed-effect Model Repeat Measurement statistical model (pharmacodynamic effects) and receiver-operating characteristic (ROC) curves (clinical outcomes association to biomarker changes). Results: Baseline (BL) characteristics were similar among treatment groups. Most patients (63%) had previously received biological therapy. At Week 12, numerically greater geometric mean changes from BL in IL-17A and IL-22 levels were seen in each miri group vs. pbo (Table 1). The area under the ROC curve (AUC) analyses of fold decrease in serum IL-17A (BL to Week 12) association with Week-12 clinical response and clinical remission using all study participants were 0.78 [0.72–0.84] and 0.71 [0.58–0.83], respectively. The ROC AUCs for fold decrease in serum IL-22 association with Week-12 clinical response and clinical remission using all study participants were 0.71 [0.64–0.78] and 0.60 [0.46–0.73], respectively. Abstract OP52 – Table 1. Conclusion: Patients who were treated with mirikizumab had greater reductions from BL in serum levels of the IL-23-dependent pro-inflammatory cytokines IL-17A and IL-22, compared with pbo. Changes in serum cytokine expression (BL to Week 12) were associated with clinical outcomes. These data confirm the biological activity of mirikizumab in patients with moderately to severely active UC.