Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD.

BACKGROUND AND OBJECTIVES: Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events. RESULTS: Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported. CONCLUSIONS: In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Intravenous iron is a key component of anemia management for chronic kidney disease (CKD). Ferumoxytol is a unique intravenous iron product that can be administered as a rapid injection in doses up to 510 mg. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, open-label, controlled, multicenter Phase 3 trial to evaluate the safety and efficacy of intravenous ferumoxytol compared with oral iron. Anemic patients with CKD stage 5D on hemodialysis and on a stable erythropoiesis-stimulating agent regimen received either two injections of 510 mg of ferumoxytol within 7 d (n = 114) or 200 mg elemental oral iron daily for 21 d (n = 116). The primary efficacy endpoint was the change in hemoglobin from baseline to day 35. Safety was closely monitored. RESULTS: Ferumoxytol resulted in a mean increase in hemoglobin of 1.02 +/- 1.13 g/dl at day 35 compared with 0.46 +/- 1.06 g/dl with oral iron (P = 0.0002). Twice as many ferumoxytol-treated patients than oral iron-treated patients achieved a > or =1 g/dl hemoglobin increase at day 35 (P = 0.0002). There was a greater mean increase in transferrin saturation (TSAT) with ferumoxytol compared with oral iron at day 35 (P < 0.0001). The larger hemoglobin increase after ferumoxytol compared with oral iron at day 35 persisted after adjustment for baseline hemoglobin, TSAT, and serum ferritin. Overall adverse event rates were comparable between groups. CONCLUSIONS: In patients on hemodialysis, rapid intravenous injection of 510 mg of ferumoxytol led to significantly greater hemoglobin increases compared with oral iron, with comparable tolerability.