title: Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.
abstract: BACKGROUND
  FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD).
  
  
  METHODS
  In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed.
  
  
  RESULTS
  In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects.
  
  
  CONCLUSIONS
  FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.
authors.affiliation: Institute of Nephrology, Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Renji Hospital, Shanghai, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Qian
authors.affiliation: Zhejiang University, Hangzhou, China.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Chen
authors.affiliation: Sun Yat-Sen University, Guangzhou, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Changzheng Hospital, Shanghai, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Mei
authors.affiliation: Shanghai Huashan Hospital, Shanghai, China.
authors.forename: Chuanming
authors.initials: C
authors.lastname: Hao
authors.affiliation: Xinhua Hospital, Jiaotong University, Shanghai, China.
authors.forename: Gengru
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Dalian Medical University, Dalian, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Lin
authors.affiliation: Shenzhen People's Hospital, Shenzhen, China.
authors.forename: Xinzhou
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Beijing University First Hospital, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zuo
authors.affiliation: Sichuan Province Hospital, Chengdu, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: He
authors.affiliation: West China Hospital, Chengdu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.affiliation: Union Medical College Hospital, Beijing, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Li
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Dalvin
authors.initials: D
authors.lastname: Ni
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: Cameron
authors.initials: C
authors.lastname: Liu
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Lynda
authors.initials: L
authors.lastname: Szczech
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Anatole
authors.initials: A
authors.lastname: Besarab
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Neff
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Kin-Hung
authors.initials: KH
authors.lastname: Peony Yu
authors.affiliation: FibroGen, Inc., San Francisco, CA, USA.
authors.forename: Frank H
authors.initials: FH
authors.lastname: Valone
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D055815:Young Adult
chemical_list: D007546:Isoquinolines; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005998:Glycine; C584543:roxadustat
keywords: FG-4592; anemia in chronic kidney disease; erythropoiesis; erythropoietin; hypoxia-inducible factor