Changes in Iron Availability with Roxadustat in Nondialysis- and Dialysis-Dependent Patients with Anemia of CKD

Abstract

Background: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin by stimulating erythropoietin synthesis, and improving iron availability through facilitation of iron uptake and/or release from stores. In this exploratory analysis, we assessed the effect of roxadustat treatment on laboratory parameters related to iron metabolism in patients with anemia of chronic kidney disease (CKD). Methods: Data were pooled from pivotal, randomized, phase 3 roxadustat trials: three placebo-controlled, double-blind trials in non-dialysis-dependent (NDD)-CKD and three open-label, active-comparator (epoetin alfa) trials in dialysis-dependent (DD)-CKD. In this exploratory analysis, mean changes from baseline in hemoglobin, iron parameters, and hepcidin, and intravenous (IV) iron use were evaluated. Pooled results in NDD-CKD and DD-CKD patients are reported. Results: Overall, 4277 patients with NDD-CKD and 3890 patients with DD-CKD were evaluated. Hemoglobin increases with roxadustat treatment were accompanied by increases in serum iron and total iron-binding capacity (TIBC) and decreases in serum ferritin and hepcidin from baseline through Week 52. With epoetin alfa, the hemoglobin increase was accompanied by decreases in serum ferritin and hepcidin, but serum iron decreased and there was no change in TIBC. With placebo, there were no changes in hemoglobin, iron parameters, or hepcidin. During treatment, IV iron use was reduced with roxadustat versus placebo and epoetin alfa. Conclusions: In patients with NDD-CKD and DD-CKD, roxadustat treatment is associated with increases in serum iron and TIBC, accompanied by reduced hepcidin and indicative of improved iron kinetics. Patients treated with roxadustat achieved target hemoglobin levels with less IV iron use versus comparators. Practitioners treating patients with anemia of CKD with roxadustat should consider its unique effects when interpreting iron parameters.

Open‐label, Phase 2 study of roxadustat for the treatment of anemia in patients receiving chemotherapy for non‐myeloid malignancies

“…This study also reported variable ferritin and serum iron results between the roxadustat 2.0‐ and 2.5‐mg/kg starting dose groups. Previous studies in patients with anemia of CKD have reported a reduction in ferritin and increase in serum iron when treated with roxadustat, 9,10,22,23 which is indicative of increased iron mobilization and utilization for erythropoiesis 24 …”

“…Previous studies in patients with anemia of CKD have reported a reduction in ferritin and increase in serum iron when treated with roxadustat, 9,10,22,23 which is indicative of increased iron mobilization and utilization for erythropoiesis. 24 In this population, most patients achieved Hb increases of ≥1, ≥1.5, and ≥2 g/dL at any point within the 16-week treatment period.…”

“…Roxadustat is an oral hypoxia‐inducible factor (HIF)‐prolyl hydroxylase (PH) inhibitor that stabilizes HIF‐α and corrects Hb by promoting erythropoiesis 6–8 . Previous studies in patients with anemia of chronic kidney disease (CKD) have demonstrated the efficacy of roxadustat in correcting Hb levels and improving iron kinetics by reducing hepcidin 6–10 . Through stabilization of HIF‐α, roxadustat also promotes angiogenesis via activation of the vascular endothelial growth factor (VEGF) pathway 11 .…”

“…[6][7][8] Previous studies in patients with anemia of chronic kidney disease (CKD) have demonstrated the efficacy of roxadustat in correcting Hb levels and improving iron kinetics by reducing hepcidin. [6][7][8][9][10] Through stabilization of HIF-α, roxadustat also promotes angiogenesis via activation of the vascular endothelial growth factor (VEGF) pathway. 11 However, roxadustat did not enhance oncogenesis in non-clinical studies, including VEGF-dependent mouse models, nor is there evidence of sustained increases in systemic VEGF levels in clinical studies of HIF-PH inhibitors.…”

A phase 3b, multicenter, open‐label, single‐arm study of roxadustat within a US dialysis organization: The DENALI study

“…Similar decreases in ferritin have been seen in earlier roxadustat studies, especially in patients with higher baseline ferritin. 24,[37][38][39] However, the DENALI study was not specifically designed to assess the impact on iron mobilization and utilization, which are both affected by multiple factors that were not systematically captured during this study.…”