- Fecal Incontinence
|Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis
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
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 firstname.lastname@example.org.
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.