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Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients

2015; Oxford University Press; Volume: 30; Issue: 10 Linguagem: Inglês

10.1093/ndt/gfv302

1460-2385

Anatole Besarab, Robert Provenzano, Joachim Hertel, Raja I. Zabaneh, Stephen J. Klaus, Tyson Lee, Robert Leong, Stefan Hemmerich, Kin-Hung P. Yu, Thomas B. Neff,

Iron Metabolism and Disorders

Background.Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis.This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects.Methods.NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/ dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat: placebo ratio of 3:1.Efficacy was assessed by (i) mean Hb change (ΔHb) from baseline (BL) and (ii) proportion of Hb responders (ΔHb ≥ 1.0 g/dL).Pharmacodynamic evaluation was performed in a subset of subjects.Safety was evaluated by adverse event frequency/severity.Results.Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy.BL characteristics for roxadustat and placebo groups were comparable.In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups.Maximum ΔHb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects.Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo.Conclusions.Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin.Adverse events were similar in the roxadustat and placebo groups.Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial.