Academic Journal
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: | Wagner, Frank, Mansfield, John C, Lekkerkerker, Annemarie N, Wang, Yehong, Keir, Mary, Dash, Ajit, Butcher, Brandon, Harder, Brandon, Orozco, Luz D, Mar, Jordan S, Chen, Hao, Rothenberg, Michael E |
| بيانات النشر: | BMJ Publishing Group Ltd |
| سنة النشر: | 2023 |
| المجموعة: | HighWire Press (Stanford University) |
| مصطلحات موضوعية: | Inflammatory bowel disease |
| الوصف: | 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 IgG 4 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 . |
| نوع الوثيقة: | text |
| وصف الملف: | text/html |
| اللغة: | English |
| Relation: | http://gut.bmj.com/cgi/content/short/72/8/1451; http://dx.doi.org/10.1136/gutjnl-2022-328387 |
| DOI: | 10.1136/gutjnl-2022-328387 |
| الاتاحة: | http://gut.bmj.com/cgi/content/short/72/8/1451 https://doi.org/10.1136/gutjnl-2022-328387 |
| Rights: | Copyright (C) 2023, BMJ Publishing Group |
| رقم الانضمام: | edsbas.41823A0D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1136/gutjnl-2022-328387 |
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