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

Abstract

BackgroundThis 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.MethodsParticipants (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.ResultsOver 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.ConclusionsDaprodustat 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.

A 24‐Week Anemia Correction Study of Daprodustat in Japanese Dialysis Patients

“…Hepcidin, ferritin, and TSAT decreased, and TIBC increased, during the 24‐week treatment period. These findings are consistent with iron utilization due to increased erythropoiesis and are aligned with findings in our previous phase 2 studies .…”

“…No death, cancer, myocardial infarction, stroke, or heart failure was observed during the 24‐week study period. No new safety concern was identified in the study, and the safety profile was comparable to that in the phase 2 studies .…”

“…Another phase 2 study in hemodialysis patients showed that daprodustat 4 to 10 mg once daily produced dosedependent changes in hemoglobin levels over the first 4 weeks after patients were switched from a stable dose of rhEPO. Target hemoglobin levels were also maintained over 24 weeks; the maximum observed plasma EPO levels in the control arm were approximately 14-fold higher than those in the daprodustat arm in this population (16). Another 4-week, phase 2 study in Japanese patients on hemodialysis with anemia who had discontinued rhEPO for 2 to 8 weeks showed that daprodustat 4 to 10 mg daily produced dose-dependent increases in hemoglobin, with a moderate increase in endogenous EPO (17).…”

“…Activation of the HIF pathway with daprodustat may theoretically increase expression of vascular endothelial growth factor (VEGF), but in our previous studies of daprodustat, the evaluated doses increased endogenous EPO only moderately without changing circulating VEGF levels . Because increases in local VEGF production may be associated with the retinal neovascularization and macular edema observed in diabetic retinopathy, choroidal leakage, edema, and neovascularization seen in age‐related macular degeneration , full ophthalmologic exams were conducted to assess whether daprodustat affected progression of macular edema, proliferative retinopathy, or choroidal neovascularization in the current study.…”

Ckj consolidation among Q1 Urology and Nephrology journals

“…Top-cited articles also included those related to CKD complications, such as cognitive function [ 6 ] and frailty [ 12 ], as well as management of complications such as pain [ 4 ] and anaemia [ 32 , 38 ]. Anaemia management focused on early clinical trials the novel drug family of oral hypoxia-inducible factor activators, such as daprodustat [ 32 , 38 ].…”