Abstract
BackgroundDaprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule.Methods103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days.ResultsMean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an Emax model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population.ConclusionsThese data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen.Trial registrationClinicalTrials.gov Identifier: NCT02689206; date registered: 02/11/2016.
Highlights
Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients
Anemia is further exacerbated by shortened erythrocyte survival, which is associated with the uremic milieu and the hemodialysis procedure [1]
One participant randomized to the placebo group erroneously received daprodustat 25 mg
Summary
Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors (PHIs) are an emerging new class of therapy for Bailey et al BMC Nephrology (2019) 20:372 the treatment of anemia of CKD. These molecules stimulate erythropoiesis through inhibition of HIF-prolyl hydroxylase domain enzymes (PHD1, PHD2, PHD3) resulting in the accumulation of HIFα transcription factors and increased expression of HIF-responsive genes under normoxic conditions [6]. HIF-responsive genes include EPO and other proteins involved in increasing oxygen availability and utilization as well as proteins involved in iron utilization, angiogenesis, apoptosis, metabolism, and vascular tone [7] Based on their mechanism of action, HIF-PHIs are postulated to be associated with fewer major adverse cardiovascular events by raising hemoglobin without the supraphysiologic EPO concentrations associated with rhEPO therapy [6]
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