title: A Novel Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial.
abstract: BACKGROUND
  Anemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (PHIs) stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI.
  
  
  METHODS
  Multicenter, single-blind, randomized, placebo-controlled, parallel-group study.
  
  
  METHODS
  Anemic non-dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n=70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n=37).
  
  
  METHODS
  Patients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25mg) once daily for 28 days.
  
  
  METHODS
  Primary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin [Hb] concentration, plasma EPO concentrations, reticulocyte count, and others]) and safety and tolerability end points were obtained.
  
  
  RESULTS
  Both CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0g/dL (CKD-3/4/5) and >0.5g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol-defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients.
  
  
  CONCLUSIONS
  Sparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses.
  
  
  CONCLUSIONS
  GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD.
authors.affiliation: Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA. Electronic address: richard.a.brigandi@gsk.com.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brigandi
authors.affiliation: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC.
authors.forename: Brendan
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Coreen
authors.initials: C
authors.lastname: Oei
authors.affiliation: Intrinsic LifeSciences, La Jolla, CA.
authors.forename: Mark
authors.initials: M
authors.lastname: Westerman
authors.affiliation: Intrinsic LifeSciences, La Jolla, CA.
authors.forename: Gordana
authors.initials: G
authors.lastname: Olbina
authors.affiliation: North Shore Hospital, Waitemata District Health Board, Auckland, New Zealand.
authors.forename: Janak
authors.initials: J
authors.lastname: de Zoysa
authors.affiliation: Renal Research, Gosford, Australia.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Roger
authors.affiliation: Osmania General Hospital, Hyderabad, India.
authors.forename: Manisha
authors.initials: M
authors.lastname: Sahay
authors.affiliation: Department of Nephrology, Christchurch Hospital.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cross
authors.affiliation: Monash University, Melbourne, Australia.
authors.forename: Lawrence
authors.initials: L
authors.lastname: McMahon
authors.affiliation: Rangadore Memorial Hospital, Bangalore, India.
authors.forename: Veerabhadra
authors.initials: V
authors.lastname: Guptha
authors.affiliation: Moscow State University of Medicine & Dentistry, Moscow, Russia.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Smolyarchuk
authors.affiliation: Pushpanjali Crosslay Hospital, Uttar Pradesh, India.
authors.forename: Narinder
authors.initials: N
authors.lastname: Singh
authors.affiliation: Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Russ
authors.affiliation: Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology*; D001463:Barbiturates / Q000627:therapeutic use*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D064800:Prolyl-Hydroxylase Inhibitors / Q000627:therapeutic use*; D051436:Renal Insufficiency, Chronic / Q000150:complications*; D016037:Single-Blind Method; D013997:Time Factors; D055815:Young Adult
chemical_list: D001463:Barbiturates; C000599718:GSK1278863; D064800:Prolyl-Hydroxylase Inhibitors; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005998:Glycine
keywords: Erythropoietin (EPO); chronic kidney disease (CKD); dialysis; dosing; erythropoiesis-stimulating agent (ESA); hemoglobin; hemoglobin response rate; hepcidin; hypoxia-inducible factor (HIF); pharmacodynamics; pharmacokinetics; phase II; prolyl hydroxylase inhibitor (PHI); randomized controlled trial (RCT); reticulocyte count