AI Article Synopsis
- The study evaluated efmarodocokin alfa, a fusion protein agonist of interleukin-22 (IL-22), to assess its safety, tolerability, and pharmacokinetics in healthy volunteers and ulcerative colitis patients over 12 weeks.
- Common adverse events included reversible dermatological issues, and dose-limiting effects were noted at higher doses, with patients showing lower drug exposure compared to healthy volunteers.
- The results indicated activation of the IL-22 receptor pathway and showed promising clinical responses in active-treated patients, suggesting further research is warranted for its potential as a non-immunosuppressive treatment for inflammatory bowel disease.
Article 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 IgG 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359578 | PMC |
| http://dx.doi.org/10.1136/gutjnl-2022-328387 | DOI Listing |
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- Common adverse events included reversible dermatological issues, and dose-limiting effects were noted at higher doses, with patients showing lower drug exposure compared to healthy volunteers.
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