• Richard A Brigandi, Brendan Johnson, Coreen Oei, Mark Westerman, Gordana Olbina, Janak de Zoysa, Simon D Roger, Manisha Sahay, Nicholas Cross, Lawrence McMahon, Veerabhadra Guptha, Elena A Smolyarchuk, Narinder Singh, Steven F Russ, Sanjay Kumar, and PHI112844 Investigators.
• Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA. Electronic address: richard.a.brigandi@gsk.com.
• Am. J. Kidney Dis. 2016 Jun 1; 67 (6): 861-71.

BackgroundAnemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (PHIs) stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI.Study DesignMulticenter, single-blind, randomized, placebo-controlled, parallel-group study.Setting & ParticipantsAnemic non-dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n=70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n=37).InterventionsPatients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25mg) once daily for 28 days.Outcomes & MeasurementsPrimary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin [Hb] concentration, plasma EPO concentrations, reticulocyte count, and others]) and safety and tolerability end points were obtained.ResultsBoth CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0g/dL (CKD-3/4/5) and >0.5g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol-defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients.LimitationsSparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses.ConclusionsGSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD.Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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