Gut. 2023 Aug;72(8):1451-1461. doi: 10.1136/gutjnl-2022-328387.Epub 2023 Feb 2.

Frank Wagner ¹, John C Mansfield ², Annemarie N Lekkerkerker ³, Yehong Wang ³, Mary Keir ³, Ajit Dash ³, Brandon Butcher ³, Brandon Harder ³, Luz D Orozco ³, Jordan S Mar ³, Hao Chen ³, Michael E Rothenberg ⁴

Author information

¹Charité Research Organization, Berlin, Germany.

²Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

³Genentech Inc, South San Francisco, California, USA.

⁴Genentech Inc, South San Francisco, California, USA rothenberg.michael@gene.com.

Abstract

Background: The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG₄ for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions.

Methods: This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30-90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort).

Results: The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 μg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients.

Conclusion: Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic.

Trial registration number: NCT02749630.