A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function
| Autor: | H. A. Stirnadel-Farrant, Mary Birchler, R. Schroyer, Christine J. Watson, Oriol Bestard, Neil S. Sheerin, Stephen DeWall, John D. Scott, Stephen J. Wigmore, Lee Abberley, R. Noble, Ewen M Harrison, Menna R. Clatworthy, Robert B. Kirkpatrick, Luke Devey, M. Busz, David B. Kingsmore, Katrina Stevenson, S. Andrews, K. S. Thorneloe, E. Wlodek, Alexander N.R. Weber, D. Krull |
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| Přispěvatelé: | Kirkpatrick, R. B. [0000-0002-8671-2361], Andrews, S. [0000-0002-5407-7201], Thorneloe, K. S. [0000-0003-3640-9839], Weber, A. [0000-0001-6952-5081], Apollo - University of Cambridge Repository, Kirkpatrick, RB [0000-0002-8671-2361], Andrews, S [0000-0002-5407-7201], Thorneloe, KS [0000-0003-3640-9839], Weber, A [0000-0001-6952-5081] |
| Rok vydání: | 2021 |
| Předmět: |
Male
Hyperkalemia Physiology medicine.medical_treatment Biopsy 030232 urology & nephrology Trasplantament renal Pilot Projects 030204 cardiovascular system & hematology Urine Biochemistry Kidney transplantation 0302 clinical medicine Clinical endpoint Renal Transplantation Medicine education.field_of_study Multidisciplinary Acute kidney injury Interleukin-18 Diàlisi Acute Kidney Injury Middle Aged Tissue Donors Body Fluids Nephrology Female medicine.symptom Anatomy Biòpsia Research Article Adult medicine.medical_specialty Science Population Urology Delayed Graft Function Surgical and Invasive Medical Procedures Antibodies Monoclonal Humanized Urinary System Procedures 03 medical and health sciences Medical Dialysis Humans Adverse effect education Immunohistochemistry Techniques Dialysis Aged Medicine and health sciences Transplantation Biology and life sciences business.industry Proteins Kidneys Organ Transplantation Renal System medicine.disease Kidney Transplantation Histochemistry and Cytochemistry Techniques Research and analysis methods Reperfusion Immunologic Techniques Interferons business Physiological Processes |
| Zdroj: | PLoS ONE, Vol 16, Iss 3, p e0247972 (2021) Dipòsit Digital de la UB Universidad de Barcelona PLoS ONE |
| ISSN: | 0272-3786 |
| DOI: | 10.17863/cam.65665 |
| Popis: | Funder: GlaxoSmithKline; funder-id: http://dx.doi.org/10.13039/100004330 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. Trial registration: NCT02723786. |
| Databáze: | OpenAIRE |
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