HIF-PHD inhibitors are structural analogs of 2-oxoglutarate and have been approved for the treatment of renal anemia in several countries.
Erythropoiesis-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. 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 10–11 g/dL, 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 (ESRD), and overall mortality.
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. HIF-PHD inhibitors (HIF-PHIs) are a new class of drugs that activate HIF transcription factors and have broad therapeutic potential in clinical medicine. As anemia therapy, HIF-PHIs promote erythropoiesis primarily through increased endogenous EPO production and modulation of iron metabolism.
HIF-PHIs reversibly inhibit HIF-PHD dioxygenases, which belong to a larger family of enzymes that utilize molecular oxygen and 2-oxoglutarate (2OG) for hydroxylation. Five compounds have been approved for marketing in Japan and one compound is also approved for marketing in China, Chile, EU and the UK.