Four-Week Studies of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia.
Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dose-dependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD.
Metabolic Pathways and Cardiovascular Therapeutic Area and Louis.2.holdstock@gsk.com.
Louis
L
Holdstock
Metabolic Pathways and Cardiovascular Therapeutic Area and.
Amy M
AM
Meadowcroft
Clinical Statistics, GlaxoSmithKline, Stockley Park, London, United Kingdom;
Rayma
R
Maier
Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, North Carolina;
Brendan M
BM
Johnson
Clinical Statistics, GlaxoSmithKline, Stockley Park, London, United Kingdom;
Delyth
D
Jones
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California;
Anjay
A
Rastogi
Pines Clinical Research, Pembroke Pines, Florida; and.
Steven
S
Zeig
Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania.
John J
JJ
Lepore
Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, King of Prussia, Pennsylvania.
Alexander R
AR
Cobitz
D000368:Aged; D000740:Anemia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D001463:Barbiturates / Q000627:therapeutic use*; D004921:Erythropoietin / Q000627:therapeutic use; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications / Q000628:therapy; D016037:Single-Blind Method; D013997:Time Factors
D001463:Barbiturates; C000599718:GSK1278863; D006454:Hemoglobins; D004921:Erythropoietin; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005998:Glycine
CKD; anemia; erythropoietin