HIF-PHD Inhibitors in Renal Anemia – Update on Phase 3 Clinical Trials

Kidney Int Suppl (2011). 2021 Apr;11(1):8-25. doi: 10.1016/j.kisu.2020.12.002. Epub 2021 Mar 18.

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

Haase VH.

HIF-PHD inhibitors in renal anemia: 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.

HIF-PHD inhibitors in renal anemia: Introduction

Anemia 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 to 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, 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.

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