POS-283 HEMOGLOBIN (HB) CORRECTION WITH ROXADUSTAT IS ASSOCIATED WITH IMPROVED IRON HOMEOSTASIS IN PATIENTS WITH NON-DIALYSIS-DEPENDENT (NDD) AND DIALYSIS-DEPENDENT (DD) CHRONIC KIDNEY DISEASE (CKD)

Abstract

Anemia in CKD is caused largely by reduced erythropoietin production, decreased bone marrow responsiveness to erythropoietin, and hepcidin-induced functional iron deficiency. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases Hb by stimulating erythropoietin synthesis, increasing bone marrow responsiveness to erythropoietin, and improving iron availability. Roxadustat also decreases hepcidin and increases the expression of genes involved in iron mobility. In this post hoc analysis, we assessed the effect of treatment with roxadustat on iron parameters in patients with NDD-CKD and DD-CKD. Patients were randomized to double-blind roxadustat or placebo in three pivotal Phase 3 NDD-CKD trials (OLYMPUS, ALPS, and ANDES) and randomized to open label roxadustat or epoetin alfa in three pivotal Phase 3 DD-CKD trials (ROCKIES, SIERRAS, and HIMALAYAS). In patients with NDD-CKD, oral iron was administered without restriction per discretion of the treating physician; intravenous (IV) iron use was limited to rescue therapy. In patients with DD-CKD, IV iron was administered per usual care in the epoetin alfa group and was restricted in the roxadustat group; oral iron was not restricted in either group. Mean changes from baseline (BL) in Hb, IV iron dose, hepcidin, and iron parameters were evaluated. Pooled results per patient population are reported. Overall, 4277 patients with NDD-CKD (roxadustat N=2391; placebo N=1886; mean BL Hb 9.1 g/dL for both groups) and 3890 patients with DD-CKD (roxadustat N=1943; epoetin alfa N=1947; mean BL Hb 9.6 g/dL for roxadustat and 9.7 g/dL for epoetin alfa), including 1530 incident dialysis patients, were evaluated. In patients with NDD-CKD, mean change in Hb from BL to Weeks 28–52 was greater with roxadustat than placebo (1.9 vs 0.2 g/dL; P<0.0001). Fewer roxadustat-treated patients required IV iron than placebo-treated patients up to Week 52 (2.6% vs 6.0%; P<0.0001). Treatment with roxadustat reduced ferritin and resulted in modest reductions in transferrin saturation (TSAT) vs placebo. Roxadustat treatment increased serum iron and total iron-binding capacity (TIBC), and reduced hepcidin compared with placebo (Figure 1). In patients with DD-CKD, mean Hb increased more from BL to Weeks 28–52 with roxadustat vs epoetin alfa (1.21 vs 0.95 g/dL; P<0.0001). Roxadustat-treated patients used less monthly IV iron compared with epoetin-alfa treated patients over Weeks 28–52 (52.2 vs 66.8 mg; P<0.0001). Roxadustat reduced ferritin compared with epoetin alfa. While no changes were seen in TSAT, roxadustat increased serum iron and TIBC, and reduced hepcidin compared with epoetin alfa (Figure 2). View Large Image Figure ViewerDownload Hi-res image Download (PPT) In both patients with NDD-CKD and DD-CKD, roxadustat facilitated iron transport and utilization resulting in increases in both serum iron and TIBC, likely driven by reduced hepcidin. Overall, despite the observed greater Hb increase from BL with roxadustat, IV iron use was reduced with roxadustat in both the NDD-CKD and DD-CKD populations.