P420 A randomised, observer-blinded phase Ib multiple, ascending dose study of UTTR1147A, an IL-22Fc fusion protein, in healthy volunteers and ulcerative colitis patients

Abstract

Abstract Background Inflammatory bowel disease (IBD) is characterised by gut dysbiosis, weakened epithelial barrier, and a dysregulated immune system. Interleukin-22 (IL-22), an IL-10 family cytokine, has demonstrated efficacy in animal IBD models by promoting intestinal epithelial repair, increasing antimicrobial peptide production, and increasing mucin production via goblet cells1. UTTR1147A is a fusion protein in which IL-22 is linked with the Fc portion of IgG4 to improve the pharmacokinetic (PK) characteristics. Methods A phase I study (NCT02749630) was conducted to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of repeat IV dosing of UTTR1147A in healthy volunteers (HV) and UC patients with centrally read Mayo endoscopic score ≥ 2. 38 HVs and 24 UC patients were given UTTR1147A or placebo at doses ranging from 30 to 90 µg/kg either biweekly or monthly (6:2 UTTR1147A: placebo per cohort). PK and serum PD (REG3A and CRP) were studied across multiple time points and the Mayo Clinic Score was evaluated at baseline, day 30 and day 85. Results Overall, UTTR1147A was safe and adequately tolerated in HV and UC patients. The most common adverse events were on-target dermatological effects (dry skin, erythema, and pruritus) that were manageable, monitorable and reversible. Dose-limiting non-serious dermatological toxicities (severe dry skin, erythema, exfoliation, and discomfort) were seen in two HVs and 1 UC patient dosed with 90ug/kg Q2wk. There were 2 unrelated serious adverse events (ankle fracture and cytomegalovirus infection) that eventually resolved. PK analyses showed that UTTR1147A exposures were, in general, dose proportional within HVs and within UC patients, with a mean elimination half-life of ~16 days and ~12 days, respectively. At the same dose level, UC patients showed relatively lower drug exposures than HVs, possibly due to faster drug clearance. Consistent with the Phase Ia2, UTTR1147A directly induced production of serum PD biomarkers REG3A and CRP at all dose cohorts tested compared with placebo. Notably, UC patients appear to have attenuated serum PD responses compared with HV. Clinical response was observed in 7/18 patients, and clinical remission in 5/18 patients treated with UTTR1147A compared with 1/6 and 0/6 placebo patients, respectively. Conclusion UTTR1147A demonstrated adequate safety and PK profile in healthy volunteers and UC patients. PD biomarker data demonstrated pharmacological activity of UTTR1147A providing evidence of IL-22R pathway activation. Together with the preliminary signals of efficacy, these data support further investigation of this potential, novel non-immunosuppressive therapy in IBD.