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Lookup NU author(s): Professor Neil Sheerin
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Introduction: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-g expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. Methods: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. Results: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-g-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. Conclusion: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population.
Author(s): Wlodek E, Kirkpatrick RB, Andrews S, Noble R, Schroyer R, Scott J, Watson CJE, Clatworthy M, Harrison EM, Wigmore SJ, Stevenson K, Kingsmore D, Sheerin NS, Bestard O, Stirnadel-Farrant HA, Abberley L, Busz M, DeWall S, Birchler M, Krull D, Thorneloe KS, Weber A, Devey L
Publication type: Article
Publication status: Published
Journal: PLoS ONE
Online publication date: 08/03/2021
Acceptance date: 11/12/2020
Date deposited: 26/02/2021
ISSN (electronic): 1932-6203
Publisher: Public Library of Science
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