A Novel Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial

Background: Anemia 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 Design: Multicenter, single-blind, randomized, placebo-controlled, parallel-group study. Setting & Participants: Anemic 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). Interventions: Patients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100 mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25 mg) once daily for 28 days. Outcomes & Measurements: Primary 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. Results: BothCKD-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 > 1.0 g/dL (CKD-3/4/5) and >0.5 g/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. Limitations: Sparse 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. Conclusions: GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.