Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants with chronic kidney disease

Abstract

Background: This study assessed the short-term safety and efficacy of daprodustat (an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor) to achieve a target hemoglobin in patients with anemia of chronic kidney disease (CKD).

Methods: Patients (n = 252) with Stages 3-5 CKD not receiving dialysis were enrolled in this 24-week, multicenter trial [hemoglobin entry criteria: 8-10 g/dL (Cohort 1) or 8-11 g/dL (Cohort 2) for recombinant human erythropoietin (rhEPO)-naïve participants; 9-10.5 g/dL (Cohort 1) or 9-11.5 g/dL (Cohort 2) for rhEPO users]. rhEPO-naïve participants were randomized 3:1 to daprodustat (1, 2 or 4 mg) or control (rhEPO per standard of care). rhEPO users were randomized 1:1 to daprodustat 2 mg or control. Study medication was titrated to maintain hemoglobin 9-10.5 g/dL (Cohort 1) or 10-11.5 g/dL (Cohort 2). Hemoglobin, iron metabolism markers and safety parameters were measured every 4 weeks.

Results: Mean hemoglobin levels at Week 24 were 10.2 g/dL (Cohort 1) and 10.9 g/dL (Cohort 2) in the daprodustat group and 10.7 g/dL (Cohort 1) and 11.0 g/dL (Cohort 2) in the control group. Participants had hemoglobin levels within the target range a median of 82% and 66% of the time between Weeks 12 and 24 in the daprodustat and control groups, respectively. The adverse event profile was consistent with clinical events in the CKD population.

Conclusions: Daprodustat effectively maintained target hemoglobin over 24 weeks in CKD patients with anemia who were rhEPO naïve or had switched from existing rhEPO therapy.

Keywords: chronic kidney disease; daprodustat; hypoxia-inducible factor; prolyl hydroxylase inhibitor; recombinant human erythropoietin.

FIGURE 1:

Study flow diagram. ^aOne participant withdrew from the study because of an AE; however, this participant’s AE was actually a protocol-defined stopping criterion and is presented here in the stopping criteria category rather than the AE category. ^bCompleted all study visits or abbreviated schedule if study medication was discontinued. ^cFifteen participants discontinued study medication because of AEs; however, five 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. ^dOne participant discontinued study medication because of an AE; however, this participant’s AE was actually a protocol-defined stopping criterion and is presented here in the stopping criteria category rather than the AE category. ^eProtocol-defined reasons for discontinuation of study medication included hemoglobin <7.5 g/dL, renal transplant, increased sPAP of ≥20 mmHg, drop of LVEF ≥10% from baseline and <50% and blood transfusion. The complete list of stopping criteria is included in Supplementary data, Item S1. IP: investigational product; PI: principal investigator.

FIGURE 2:

Mean and 95% confidence interval for hemoglobin over time by original (A) and amended (B) hemoglobin criteria for the rhEPO-naïve group and original (C) and amended (D) hemoglobin criteria for the rhEPO user group. For Cohort 1, the hemoglobin entry criterion was 8–10 g/dL in the rhEPO-naïve group and 9–10.5 g/dL in rhEPO users, and the hemoglobin target range was 9–10.5 g/dL. For Cohort 2, the hemoglobin entry criterion was 8–11 g/dL in the rhEPO-naïve group and 9–11.5 g/dL in rhEPO users, and the hemoglobin target range was 10–11.5 g/dL. ^aBaseline values were calculated as the average of measurements at Week-4 and Day 1. BL, baseline; rhEPO, recombinant human erythropoietin.

FIGURE 3:

Geometric mean and 95% confidence interval for hepcidin (µg/L) by visit [intent-to-treat (ITT) population].