Sanghani NS, Haase VH.

Abstract

Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral HIF-PHIs-daprodustat, roxadustat, and vadadustat-have now advanced to global phase III clinical development culminating in the recent licensing of roxadustat for oral anemia therapy in China. Here, we survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages, and deliberate over safety concerns regarding long-term administration in patients with renal anemia.

Introduction

Anemia of chronic kidney disease (CKD) is a common complication of advanced renal failure and is primarily due to the inability of the diseased kidney to adequately respond to hypoxia and/or anemia with appropriate increases in erythropoietin (EPO) production. Widespread use of EPO replacement therapy consisting of either recombinant human EPO (rhEPO) or re-engineered preparations of recombinant EPO, collectively referred to erythropoietin stimulating agents (ESA), improved overall quality of life in some studies andreduced anemia-associated cardiovascular morbidity and the need for blood transfusions. Despite its clinical success, several large studies have established that liberal administration and supraphysiologic dosing of ESA was associated with increased risk of cardiovascular events, CKD progression, vascular access thrombosis and overall mortality.

Cardiovascular safety concerns and complications from current therapy have provided a strong incentive to develop alternative strategies for the treatment of renal anemia. While several novel approaches are under investigation in preclinical models and early phase clinical trials, the class of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) has advanced to phase III of global clinical development culminating in the recent approval of FibroGen’s compound FG-4592 (roxadustat) for marketing in China. HIF-PHIs reversibly inhibit prolyl hydroxylase domain (PHD) dioxygenases, which act as cellular oxygen sensors and control the activity of HIF, a transcription factor that regulates, among other processes, renal and hepatic EPO production and iron metabolism. In this review we survey current clinical experience with HIF-PHIs, discuss their potential advantages over current anemia therapy, and address potential safety concerns regarding their long-term use in patients with renal anemia.