Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis

Abstract

Background: This study evaluated the hemoglobin dose response, other efficacy measures and safety of daprodustat, an orally administered, hypoxia-inducible factor prolyl hydroxylase inhibitor in development for anemia of chronic kidney disease.

Methods: Participants (n = 216) with baseline hemoglobin levels of 9-11.5 g/dL on hemodialysis (HD) previously receiving stable doses of recombinant human erythropoietin (rhEPO) were randomized in a 24-week dose-range, efficacy and safety study. Participants discontinued rhEPO and then were randomized to receive daily daprodustat (4, 6, 8, 10 or 12 mg) or control (placebo for 4 weeks then open-label rhEPO as required). After 4 weeks, doses were titrated to achieve a hemoglobin target of 10-11.5 g/dL. The primary outcome was characterization of the dose-response relationship between daprodustat and hemoglobin at 4 weeks; additionally, the efficacy and safety of daprodustat were assessed over 24 weeks.

Results: Over the first 4 weeks, the mean hemoglobin change from baseline increased dose-dependently from -0.29 (daprodustat 4 mg) to 0.69 g/dL (daprodustat 10 and 12 mg). The mean change from baseline hemoglobin (10.4 g/dL) at 24 weeks was 0.03 and -0.11 g/dL for the combined daprodustat and control groups, respectively. The median maximum observed plasma EPO levels in the control group were ∼14-fold higher than in the combined daprodustat group. Daprodustat demonstrated an adverse event profile consistent with the HD population.

Conclusions: Daprodustat produced dose-dependent changes in hemoglobin over the first 4 weeks after switching from a stable dose of rhEPO as well as maintained hemoglobin target levels over 24 weeks.

Keywords: anemia; chronic kidney disease; daprodustat; hemodialysis; recombinant human erythropoietin.

FIGURE 1:

Study flow diagram.^aCompleted all study visits or abbreviated schedule if study medication was discontinued. ^bTwenty-two participants discontinued study medication because of AEs; however, 12 of these participants had AEs that were actually protocol-defined stopping criteria and are presented here in the stopping criteria category rather than the AE category. Protocol-defined stopping criteria are detailed in the Supplementary data, Item S1. IP, investigational product; PI, principal investigator.

FIGURE 2:

Mean change in hemoglobin levels from baseline to Week 4 by treatment group [intent-to-treat (ITT) population].

FIGURE 3:

Mean hemoglobin levels over 24 weeks by combined daprodustat groups versus controls [intent-to-treat (ITT) population]. BL, baseline.

FIGURE 4:

Mean hepcidin levels over 24 weeks by combined daprodustat groups versus controls [intent-to-treat (ITT) population].