Wlodek, E.Kirkpatrick, R. B.Andrews, SusanNoble, R.Schroyer, R.Scott, J.Watson, C. J. E.Clatworthy, M.Harrison, E. M.Wigmore, S. J.Stevenson, K.Kingsmore, D.Sheerin, N. S.Bestard Matamoros, OriolStirnadel-Farrant, H. A.Abberley, L.Busz, M.Dewall, S.Birchler, M.Krull, D.Thorneloe, K. S.Weber, A.Devey, L.2021-04-162021-04-162021-03-08https://hdl.handle.net/2445/176247Introduction: 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-γ 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-γ-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.23 p.application/pdfengcc by (c) Wlodek et al., 2021http://creativecommons.org/licenses/by/3.0/es/Trasplantament renalBiòpsiaDiàlisiKidney transplantationBiopsyDialysisinfo:eu-repo/semantics/article2021-04-16info:eu-repo/semantics/openAccess33684160