Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

Abstract

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a promising new class of orally administered drugs currently in late-stage global clinical development for the treatment of anemia of chronic kidney disease (CKD). HIF-PHIs activate the HIF oxygen-sensing pathway and are efficacious in correcting and maintaining hemoglobin levels in patients with non-dialysis-and dialysis-dependent CKD. In addition to promoting erythropoiesis through the increase in endogenous erythropoietin production, HIF-PHIs reduce hepcidin levels and modulate iron metabolism, providing increases in total iron binding capacity and transferrin levels, and potentially reducing the need for i.v. iron supplementation. Furthermore, HIF-activating drugs are predicted to have effects that extend beyond erythropoiesis. This review summarizes clinical data from current HIF-PHI trials in patients with anemia of CKD, discusses mechanisms of action and pharmacologic properties of HIF-PHIs, and deliberates over safety concerns and potential impact on anemia management in patients with CKD.

Treatment of Anemia in Kidney Disease: Beyond Erythropoietin

“…Based on this mechanism of action, these compounds are known as HIF-PH inhibitors (HIF-PHIs). 31,[33][34][35] There are three domains of PH: PHD-1, PHD-2, and PHD-3; HIF-PHIs under development have differing specificities for these PHDs 35,36 Phase 3 programs with 6 HIF-PHIs are ongoing or have been completed. The pharmacologic characteristics of these agents are summarized in Table 1.…”

“…On the basis of this mechanism of action, these compounds are known as HIF-PH inhibitors (HIF-PHIs). 31 , 33 , 34 , 35 …”

“…PH has 3 domains: PHD-1, PHD-2, and PHD-3, and the HIF-PHIs under development have differing specificities for these PHDs. 35 , 36 Phase 3 programs with 6 HIF-PHIs are ongoing or have been completed. The pharmacologic characteristics of these agents are summarized in Table 1 .…”

“…The pharmacologic characteristics of these agents are summarized in Table 1 . 34 , 35 As of this writing, 4 agents have been licensed in Japan: roxadustat, vadadustat, daprodustat, and enarodustat. Roxadusat is licensed in China and Chile.…”

“… a Adapted from Sanghani and Haase 34 and Haase. 35

Figure 3 Hypoxia-inducible factor (HIF) pathway. DcytB, duodenal cytochrome B; DMT, divalent metal transporter; EPO, erythropoietin; O 2 , oxygen; PH, prolyl hydroxylase.

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