title: Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients.
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.
  
  
  BACKGROUND
  Clintrials.gov #NCT00761657.
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Anatole
authors.initials: A
authors.lastname: Besarab
authors.affiliation: St Clair Specialty Physicians, Detroit, MI, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Provenzano
authors.affiliation: Kidney Care Associates, LLC, Augusta, GA, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hertel
authors.affiliation: Northwest Louisiana Nephrology, Shreveport, LA, USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Zabaneh
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Klaus
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Tyson
authors.initials: T
authors.lastname: Lee
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Leong
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hemmerich
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Kin-Hung Peony
authors.initials: KH
authors.lastname: Yu
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Neff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006454:Hemoglobins / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D006454:Hemoglobins; D064451:Hepcidins; D007546:Isoquinolines; D004921:Erythropoietin; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005998:Glycine; C584543:roxadustat
keywords: HIF-PHI; anemia; chronic kidney disease; erythropoietin; hepcidin