Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis
| العنوان: | Dose escalation randomised study of efmarodocokin alfa in healthy volunteers and patients with ulcerative colitis |
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| المؤلفون: | Frank Wagner, John C Mansfield, Annemarie N Lekkerkerker, Yehong Wang, Mary Keir, Ajit Dash, Brandon Butcher, Brandon Harder, Luz D Orozco, Jordan S Mar, Hao Chen, Michael E Rothenberg |
| المصدر: | Gut. :gutjnl-2022 |
| بيانات النشر: | BMJ, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Gastroenterology |
| الوصف: | BackgroundThe 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 IgG4for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions.MethodsThis 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).ResultsThe 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.ConclusionEfmarodocokin 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 numberNCT02749630. |
| تدمد: | 1468-3288 0017-5749 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::99867f36924e2c27e9eb200a19c1ef7b https://doi.org/10.1136/gutjnl-2022-328387 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........99867f36924e2c27e9eb200a19c1ef7b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14683288 00175749 |
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