Effects of Daprodustat, a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Anemia Management in Japanese Hemodialysis Subjects

Abstract

Background: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for treatment of anemia associated with chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients with anemia has not been previously investigated. Methods: We evaluated the relationship between daprodustat dose and hemoglobin response in Japanese patients on hemodialysis (HD) with anemia in a 4-week, phase II, double-blind, placebo-controlled study. After interrupting their erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or 10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) levels during therapy were evaluated. Results: Eighty-six of 97 randomized subjects completed the study. Mean baseline hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week administration, mean hemoglobin changes were -0.28, -0.01, 0.54, and 0.97 g/dL in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for placebo. Dose-dependent increase in plasma EPO concentration were observed up to 8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF concentrations were minimally changed, even though 5 subjects treated with 6-10 mg reached EPO >500 mIU/mL. Conclusion: Daprodustat 4-10 mg once-daily produced dose-dependent increase in hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in the study have moderately increased endogenous EPO without changes in circulating VEGF levels.

Novel Compound Induces Erythropoietin Secretion through Liver Effects in Chronic Kidney Disease Patients and Healthy Volunteers

“…High doses of TP0463518 in CKD patients tended to increase the number of reticulocytes, which was sufficient to increase Hb in other HIF-PHIs studies [13,14]. The glycosylation pattern of EPO derived from the liver is different from that of EPO derived from the kidney.…”

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

“…According to the existing body of evidence from the published literature, daprodustat has thus far demonstrated the potential to be an effective alternative for the treatment of anemia in patients with CKD [15,16,18]. Daprodustat exhibited dose-dependent EPO and non-EPO response mechanisms for effectively increasing and maintaining Hb levels.…”

“…Management of anemia in hemodialysis (HD) patients: 4, 6, 8 and 10 mg A phase II, randomized, placebo-controlled, dose ranging study of daprodustat was conducted in Japanese patients on HD (NCT0201971) [18]. In a phase I trial of daprodustat conducted in healthy volunteers, Japanese patients had a 1.3 to 1.5 fold higher plasma drug concentration [14].…”

“…In a phase I trial of daprodustat conducted in healthy volunteers, Japanese patients had a 1.3 to 1.5 fold higher plasma drug concentration [14]. This study sought to evaluate the Hb dose response and safety of daprodustat in Japanese participants [14,18]. The study randomized 97 Japanese participants who had been on HD for ≥ 8 weeks and who were effectively managed with an ESA resulting in stable Hb levels.…”

“…Other secondary endpoints included iron parameters [18]. A total of 5% and 20% of participants received stable oral or IV iron supplementation throughout the study.…”