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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/176247
A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function
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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-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.
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WLODEK, E., KIRKPATRICK, R. b., ANDREWS, Susan, NOBLE, 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, Oriol, STIRNADEL-FARRANT, H. a., ABBERLEY, L., BUSZ, M., DEWALL, S., BIRCHLER, M., KRULL, D., THORNELOE, K. s., WEBER, A., DEVEY, L.. A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function. _PLoS One_. 2021. Vol. 16, núm. 3, pàgs. e0247972. [consulta: 25 de febrer de 2026]. [Disponible a: https://hdl.handle.net/2445/176247]