Abstract
Introduction
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.
P502 Ulcerative colitis patients on vedolizumab lacking response at induction phase continue to improve over the first 6 months of treatment
