Four-Week Studies of Oral Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia

Abstract

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 dosedependent 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. 27: 123427: -124427: , 201627: . doi: 10.1681 Advanced CKD is frequently associated with anemia 1,2 and its pathogenesis is multifactorial, inclusive of a relative deficiency of erythropoietin (EPO) and impaired absorption and utilization of iron. 3 Current guidelines and recommendations for anemia management in CKD advise treatment with supplemental iron and recombinant human erythropoietins (rhEPOs) if appropriate. rhEPO therapy led to a correction of hemoglobin levels in the majority of dialysis patients 12 and a reduction in the need for red blood cell transfusions. 12 However, several large randomized trials of rhEPO have reported adverse cardiovascular outcomes. The Normal Hematocrit Study, which aimed to normalize hematocrit at 42% versus maintaining it at 30%, was terminated early because of concerns from the independent data monitoring committee around the higher all-cause mortality rate in the normal hematocrit arm compared with the low hematocrit arm, even though the prespecified termination criterion of an overall 5% significance was not met. The Correction of Hemoglobin and Outcomes in Renal Insufficien...

An Emerging Treatment Alternative for Anemia in CKD Patients: A Review on Daprodustat

“…Conversely, daprodustat demonstrated a dosedependent decrease in hepcidin concentration with a subsequent trend towards baseline during follow-up periods [15,16]. Additionally, daprodustat decreased the concentration of ferritin at all doses, which signifies utilization of iron stores [15,16].…”

“…Conversely, daprodustat demonstrated a dosedependent decrease in hepcidin concentration with a subsequent trend towards baseline during follow-up periods [15,16]. Additionally, daprodustat decreased the concentration of ferritin at all doses, which signifies utilization of iron stores [15,16]. Surrogate markers of pharmacodynamic effects, including EPO, VEGF, and absolute reticulocyte counts, have also exhibited dose-ordered increases over a range of 10 to 100 mg in both Japanese and Caucasian ethnic populations [14].…”

“…Daprodustat demonstrated an appreciable dose-dependent increase in a variety of pharmacodynamic markers, including EPO concentration, absolute reticulocyte count, Hb level, total iron-binding capacity (TIBC), and unsaturated iron-binding capacity in target populations [15,16]. Conversely, daprodustat demonstrated a dosedependent decrease in hepcidin concentration with a subsequent trend towards baseline during follow-up periods [15,16].…”

“…Studies 1 and 2: 0.5, 2 and 5 mg: Two additional phase II A randomized, blinded, controlled studies were conducted with daprodustat over a 4 week time period in separate populations with CKD to further evaluate the safety and efficacy of daprodustat [16]. The first study, referred to as the 'nondialysis study' was conducted in participants with CKD stages 3-5 not undergoing dialysis who had not used recombinant human erythropoietin (rhEPO) within the past 7 weeks (NCT01587898).…”

“…The most commonly reported side effect was nausea [15,16]. However, due to protocol defined safety criteria, a considerable amount of patients were withdrawn from these studies because of a robust pharmacodynamic Hb response, indicating a potential for long-term cardiovascular and/or malignant events that have yet to be uncovered given the short time frame for these trials [15,16].…”