30, 31 Further studies demonstrated that in addition to the hypoxic induction of EPO in the kidney and liver, HIF-1 played a more general role, regulating hypoxia-sensitive genes, including those encoding glycolytic enzymes (e.g., phosphoglycerate kinase 1 and lactate dehydrogenase A) and angiogenic factors, such as vascular endothelial growth factor (VEGF). 29 HIF-1 was subsequently purified from large-scale HeLa and Hep3B cell cultures, sequenced, and found to consist of 2 protein subunits, HIF-1α and HIF-1β (described below). 27 This discovery facilitated the identification and characterization of a regulatory DNA sequence located within the 3′ enhancer region of the EPO gene, 28 which was shown to bind a nuclear factor under hypoxia, named HIF-1. 25, 26 The molecular mechanisms that regulate the hypoxic induction of EPO, however, were not understood until the discovery that human hepatoma cells were capable of producing EPO under hypoxic conditions. This response is mediated by the glycoprotein hormone EPO, which was purified from the urine of patients with aplastic anemia in 1977 24 the EPO gene was cloned in 1985. This review discusses the mechanisms of action and pharmacologic properties of HIF-PHIs, summarizes clinical data from HIF-PHI trials in patients with anemia of CKD, and considers their clinical efficacy, safety, and potential advantages compared with the current standard of care.Ī classic response to hypoxia is the increase in red blood cell mass. 22, 23 Licensing of HIF-PHIs is expected soon in North America and Europe. 21 Roxadustat is also approved for marketing in China. Four compounds are approved for marketing in Japan: daprodustat (Duvroq, Kyowa Kirin Co., Ltd.), 13, 14, 15 roxadustat (Evrenzo, Astellas Pharma for dialysis-dependent CKD), 16, 17, 18 vadadustat (Vafseo, Akebia Therapeutics), 19, 20 and enarodustat (Enaroy, Japan Tobacco Inc.). 12 HIF-PHIs are currently in advanced global clinical development for anemia management in patients with CKD. HIF-PHIs reversibly inhibit HIF-PHD dioxygenases, which belong to a larger family of enzymes that utilize molecular oxygen and 2-oxoglutarate for hydroxylation. 11 As anemia therapy, HIF-PHIs promote erythropoiesis primarily through increased endogenous EPO production and modulation of iron metabolism. 10 HIF-PHD inhibitors (HIF-PHIs) are a new class of drugs that activate HIF transcription factors and have broad therapeutic potential in clinical medicine. The hypoxia-inducible factor (HIF)–prolyl hydroxylase domain (PHD) pathway regulates cellular responses to hypoxia and is involved in multiple diseases, including anemia, polycythemia, ischemic diseases, pulmonary arterial hypertension, and cancer. 1, 2 Although ESAs have decreased blood transfusion needs, reduced cardiovascular morbidity and mortality, and improved symptoms associated with severe anemia of CKD with hemoglobin (Hb) target levels of 10 to 11 g/dl, 3, 4, 5, 6 higher Hb target levels (i.e., ≥13 g/dl) increase the risk for cardiovascular and cerebrovascular events, vascular access thrombosis, progression to end-stage renal disease, and overall mortality. 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.Įrythropoiesis-stimulating agents (ESAs) are recombinant versions of human erythropoietin (EPO) and the current mainstay of treatment for anemia of chronic kidney disease (CKD), typically in conjunction with iron supplementation. Furthermore, HIF-activating drugs are predicted to have effects that extend beyond erythropoiesis. 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. 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. 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).
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