A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

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.
Competing Interests: SA, RN, RS, HAS-F, LA, MBusz, SDW, MBirchler, DKrull, and AW are employees of and stockholders in GSK. RBK, RN, KST and LD are previous employees of GSK and hold stocks. EW is a PhD student with GSK. EMH has received advisory board support from GSK. JS is a former employee of GSK with shares in GSK and Director of JMS Statistics Ltd, which had a contract of service with SRG, who were paid fees by GSK and in turn paid fees to JMS Statistics Ltd. JS is now an employee of Orange Genie, which had a contract of service with SRG, who are paid fees by GSK. CJW has received an honorarium from GSK for attending an advisory board in connection with GSK1070806 anti-IL18 antibody. KS has received travel expenses from GSK for an investigator meeting. MC has received consulting fees from GSK. SJW, DKingsmore, OB and NSS have no conflicts of interest to declare. This does not alter our adherence to PLoS One policies on sharing data and materials.