Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study

Abstract

BackgroundCurrent anemia therapies for patients with non–dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis.MethodsIn this double-blind phase 3 study, we randomized patients with non–dialysis-dependent CKD stages 3–5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28–52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events.ResultsThe study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%).ConclusionsRoxadustat effectively increased hemoglobin in patients with non–dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo.Clinical Trial registry name and registration number:Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627

Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES)

“…Previously, among Japanese NDD CKD patients not receiving ESAs, the Hb response rate from BL to Week 24 was 94.9% in roxadustat-treated patients [ 13 ]. When roxadustat was compared with placebo in Chinese [ 14 ] and European [ 15 , 16 ] NDD CKD patients with anaemia, Hb response occurred in more roxadustat patients (75.0–86.0%), compared with placebo patients (0.0–8.5%). Additionally, roxadustat demonstrated non-inferiority for Hb maintenance rate versus DA in Japanese patients on haemodialysis [ 11 ] and versus epoetin alfa in global studies of DD patients [ 8 ].…”

Safe and Effective Treatment for Anemic Patients With Chronic Kidney Disease: An Updated Systematic Review and Meta-Analysis on Roxadustat

“…Roxadustat Increased the Level of Hemoglobin in Non-Dialysis-Dependent Chronic Kidney Disease Patients With Elevated C-reactive Protein Levels Inflammation, which causes iron retention, increased hepcidin formation and impaired erythroid progenitor proliferation was believed as a major contributing factor to anemia (Macdougall et al, 2016;Weiss et al, 2019). In order to assess the influence of inflammation on the effect of roxadustat, we extracted Hb changes in subjects with baseline CRP > ULN from six trials (Chen et al, 2019a;Akizawa et al, 2019c;NCT02174731, 2020;Coyne et al, 2021;Fishbane et al, 2021;Provenzano et al, 2021) (four trials for DD-CKD patients, two trials for NDD-CKD patients). The pooled results showed that for patients with baseline CRP upper than ULN, there was a significant rise of Hb level with the use of roxadustat compared with ESAs and placebo (WMD: 0.63; 95% CI: 0.09-1.17; p 0.02; with heterogeneity [p < 0.00001]; Figure 5 and Table 3).…”

“…In addition, the duration of the studies enrolled in previous meta-analyses was relatively short, with a maximum follow-up of 26 weeks. Recently, the results of five large phase 3 clinical trials Akizawa et al (2020a), Coyne et al (2021), Fishbane et al (2021), Provenzano et al (2021), Shutov et al (2021) of roxadustat were released, so we updated the meta-analysis. Randomized controlled trials that assessed the efficacy (hemoglobin levels and response) and safety (treatment-emergent adverse events) of roxadustat in DD-CKD and NDD-CKD anemia patients comparing with ESAs or placebo were retriedved with an aim to generate a robust conclusion on the effect of and safety of roxadustat.…”

Kidney-Targeted Delivery of Prolyl Hydroxylase Domain Protein 2 Small Interfering RNA with Nanoparticles Alleviated Renal Ischemia/Reperfusion Injury

“…Multiple trials have demonstrated that inhibition of PHD effectively improve anemia in those patients with less adverse effects (Akizawa et al, 2020a;Akizawa et al, 2020b;Fishbane et al, 2021). There is no clinical research about effect of PHD inhibition on AKI.…”