A Novel Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial

  • Am J Kidney Dis. 2016 Jun;67(6):861-71. doi: 10.1053/j.ajkd.2015.11.021.
Richard A Brigandi  1 ,  Brendan Johnson  2 ,  Coreen Oei  3 ,  Mark Westerman  4 ,  Gordana Olbina  4 ,  Janak de Zoysa  5 ,  Simon D Roger  6 ,  Manisha Sahay  7 ,  Nicholas Cross  8 ,  Lawrence McMahon  9 ,  Veerabhadra Guptha  10 ,  Elena A Smolyarchuk  11 ,  Narinder Singh  12 ,  Steven F Russ  3 ,  Sanjay Kumar  3 ,  PHI112844 Investigators
Affiliations
  • 1. Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA. Electronic address: [email protected].
  • 2. Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC.
  • 3. Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA.
  • 4. Intrinsic LifeSciences, La Jolla, CA.
  • 5. North Shore Hospital, Waitemata District Health Board, Auckland, New Zealand.
  • 6. Renal Research, Gosford, Australia.
  • 7. Osmania General Hospital, Hyderabad, India.
  • 8. Department of Nephrology, Christchurch Hospital.
  • 9. Monash University, Melbourne, Australia.
  • 10. Rangadore Memorial Hospital, Bangalore, India.
  • 11. Moscow State University of Medicine & Dentistry, Moscow, Russia.
  • 12. Pushpanjali Crosslay Hospital, Uttar Pradesh, India.
PMID: 26827289 DOI: 10.1053/j.ajkd.2015.11.021
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.

Study design: Multicenter, single-blind, randomized, placebo-controlled, parallel-group study.

Setting & participants: 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).

Interventions: 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.

Outcomes & measurements: 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.

Limitations: 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.

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.
Products