Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6-to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study

Background: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. Study Design: Phase 2, randomized (3: 1), open-label, active-comparator, safety and efficacy study. Setting & Participants: Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. Intervention: Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0 mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. Outcomes: Primary end point was Hb level response, defined as end-of-treatment Hb level change (Delta Hb) of -0.5 g/dL or greater from baseline (part 1) and as mean Hb level >= 11.0 g/dL during the last 4 treatment weeks (part 2). Measurements: Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). Results: Baseline epoetin alfa doses were 138.3 +/- 51.3 (SD) and 136.3 +/- 47.7 U/kg/wk in part 1 and 152.8 +/- 80.6 and 173.4 +/- 83.7 U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0 mg/kg compared to 33% in the epoetin alfa control arm (P = 0.03). Hepcidin level reduction was greater at roxadustat 2.0 mg/kg versus epoetin alfa (P < 0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was w1.7 mg/kg. The least-squares-mean DHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5 g/dL) and the least-squares-mean difference in DHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. Limitations: Short treatment duration and small sample size. Conclusions: In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels. Am J Kidney Dis. 67(6): 912-924. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.