P633 Sustained reduction of IL-23-related cytokines IL-17A and IL-22 in a phase 2 study of mirikizumab in the treatment of patients with moderately-to-severely active ulcerative colitis through week 52
G.R. D’Haens1, B.E. Sands2, T. Kobayashi3, J.L. Tuttle4, J. Schmitz5, R. Higgs5, S. Ho5, S.E. Sissons5, W.J. Sandborn6
1Amsterdam University Medical Centers, Inflammatory Bowel Disease Centre, Amsterdam, The Netherlands, 2Icahn School of Medicine at Mount Sinai, Division of Gastroenterology, New York NY, USA, 3Kitasato University Kitasato Institute Hospital, Center for Advanced IBD Research and Treatment, Tokyo, Japan, 4Eli Lilly and Company, Lilly Biotechnology Center, San Diego CA, USA, 5Eli Lilly and Company, Lilly Biomedicines, Indianapolis IN, USA, 6University of California San Diego, Division of Gastroenterology, La Jolla CA, USA, Background
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 in patients with moderate-to-severely active UC during 52 weeks (weeks) of a Phase 2 randomised clinical trial (AMAC, NCT02589665). Exploration of IL-23 pathway biomarkers supports an understanding of drug activity and mechanism of action. These analyses describe exploratory biomarker results in plasma for IL-23 pathway cytokines, IL-22 and IL-17A, in subjects that responded to miri induction treatment and continued with maintenance treatment up to Week 52.
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 placebo (pbo) (N=63), miri 50mg (N=63) or 200mg (N=62) with possibility of exposure-based (EB) increases, or fixed miri 600mg (N=61) every 4 weeks, with efficacy assessment at Week 12. Miri-treated patients who achieved a clinical response at Week 12 were re-randomised 1:1 into a double-blind maintenance period to receive miri 200mg subcutaneously every 4 weeks (Q4W; N=47) or every 12 weeks (Q12W; N=46), and were treated through Week 52. Plasma EDTA samples were collected at Weeks 0, 4, 12, 24, and week 52 to evaluate circulating levels of IL-17A and IL-22.
Results
Baseline (BL) characteristics of patients who entered the maintenance period were similar between groups. At BL, 52.7% had previously received a biologic. At Week 52, 46.8% of patients in the Q4W group and 37.0% in the Q12W group were in clinical remission. Initial reductions in median IL-17A and IL-22 plasma concentrations during the induction phase were observed in the combined miri re-randomised treated groups (50 mg, 200 mg, 600 mg to either 200 mg Q4W, or Q12W) with −86.2/−59.0 % change from BL to Week 12 in the 200 mg Q4W group and −141.1/−55.8 % change from BL in the 200mg Q12W group (Figure). At Week 52, further numerical reductions from Week 12 in IL-17A and IL-22 levels were observed with −74.4/−32.1% change from Week 12 in the 200 mg Q4W group and −69.8%/−47.7% change from Week 12 in the 200 mg Q12W group.
Conclusion
Patients treated with maintenance mirikizumab had further reductions in plasma levels of the IL-23-dependent pro-inflammatory cytokines, IL-17A and IL-22, beyond that initially observed in the induction phase. These data suggest sustained biologic activity of mirikizumab in patients with moderately-to-severely active UC during maintenance. Treatment with mirikizumab for 52 weeks leads to normal, or near normal (as observed in healthy volunteer plasma) circulating levels of IL-17A and IL-22.