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

Nephrol Dial Transplant. 2015 Oct;30(10):1665-73. doi: 10.1093/ndt/gfv302. Epub 2015 Aug 3.

Abstract

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.

Clinical trials registration: Clintrials.gov #NCT00761657.

Keywords: HIF-PHI; anemia; chronic kidney disease; erythropoietin; hepcidin.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia / drug therapy*
  • Anemia / etiology
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Erythropoiesis / drug effects
  • Erythropoietin / metabolism
  • Female
  • Glycine / analogs & derivatives*
  • Glycine / therapeutic use
  • Hemoglobins / metabolism
  • Hepcidins / metabolism
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Isoquinolines / therapeutic use*
  • Male
  • Middle Aged
  • Prognosis
  • Renal Dialysis
  • Renal Insufficiency, Chronic / complications*
  • Single-Blind Method
  • Young Adult

Substances

  • FG-4592
  • Hemoglobins
  • Hepcidins
  • Isoquinolines
  • Erythropoietin
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Glycine

Associated data

  • ClinicalTrials.gov/NCT00761657