Treatment of Renal Anemia with Roxadustat: Advantages and Achievement

Abstract

Background: Although renal anemia has attracted widespread attention, a large proportion of chronic kidney disease (CKD) patients with anemia still do not meet the hemoglobin (Hb) targets. The discovery of prolyl hydroxylase domain (PHD) enzymes as regulators of hypoxia-inducible factor (HIF)-dependent erythropoiesis has led to the development of novel therapeutic agents for renal anemia. Roxadustat, the first small-molecule HIF-PHD inhibitor, has completed the phase 3 trials. There are currently more than 15 phase 3 clinical trials worldwide assessing the efficacy and safety of roxadustat in CKD patients with anemia. This review will summarize recent findings of roxadustat in the treatment of renal anemia.

Summary: Although the administration of erythropoiesis-stimulating agents (ESAs) and iron supplementation are a well-established and highly effective therapeutic approach for renal anemia, there are several safety concerns. Current findings from phase 2 and 3 trials suggest that roxadustat is clinically effective and well tolerated. On the one hand, roxadustat could increase endogenous erythropoietin (EPO) levels within or near physiological range in a titratable manner by inducing HIF pathway activation transiently. On the other hand, roxadustat also improves iron metabolism by decreasing serum hepcidin and increasing intestinal iron absorption, which is beneficial to functional iron deficiency and absolute iron deficiency. More importantly, the erythropoietic response of roxadustat is independent of baseline inflammatory state of CKD patients. Thus, the discovery of roxadustat will revolutionize the treatment strategy for renal anemia.

Key messages: Roxadustat is an emerging and promising therapeutic approach against anemia in CKD patients, which differs from those of conventional ESAs. Roxadustat corrects anemia of CKD patients through multiple pathways, beyond elevating EPO levels within physiological range, and also by handling iron metabolism (particularly decreasing the hepcidin levels). Furthermore, the Hb response of roxadustat is independent of the inflammatory microenvironment.

Keywords: Erythropoietin; Hepcidin; Iron metabolism; Renal anemia; Roxadustat.

Fig. 1

HIF coordinates erythropoietin production with iron metabolism. The oxygen-dependent PHDs as key regulators of HIF-dependent erythropoiesis became the direct therapeutic target for anemia correction. HIF-PHIs stabilize HIF via suppressing the function of PHDs directly. EPO synthesis could be stimulated by HIF (induced by pharmacologic PHD inhibition) in kidney and liver, which plays a central role in stimulating erythropoiesis in the bone marrow. In the duodenum, it is well recognized that DCYTB, DMT1, and FPN are regulated by HIF-2. DCYTB reduces Fe³⁺ to Fe²⁺, which then enters enterocytes via DMT1. Iron is then released into the circulation via FPN. The increasing evidence demonstrated that HIF activation could suppress hepcidin expression, which increases FPN expression on enterocytes, hepatocytes, and macrophages, resulting in increased iron absorption and mobilization from internal stores. HRE, hypoxia response element; DCYTB, duodenal cytochrome b reductase 1; DMT1, divalent metal transporter-1; EPO, erythropoietin; EPOR, erythropoietin receptor; RBC, red blood cell; HIF, hypoxia-inducible factor; FPN, ferroportin; Fe²⁺, ferrous iron; Fe³⁺, ferric iron.

Fig. 2

Key milestones in the development of roxadustat for the treatment of anemia caused by CKD. CFDA, China Food and Drug Administration; DD-CKD, dialysis-dependent chronic kidney disease; NDA, new drug application; US, United States; NDD-CKD, non-dialysis-dependent chronic kidney disease.