Hypoxia-Inducible Factor–Prolyl Hydroxyl Domain Inhibitors: From Theoretical Superiority to Clinical Noninferiority Compared with Current ESAs?

Anemia is a common complication of chronic kidney disease; it is mainly treated with erythropoiesis-stimulating agents (ESAs) and iron. Experimental studies extensively investigated the mechanisms involved in the body’s response to hypoxia and led to the discovery of the hypoxia-inducible factor (HIF) pathway and the enzymes regulating its function. HIF-prolyl-hydroxyl domain (PHD) inhibitors are a new class of oral drugs developed to treat anemia in chronic kidney disease. By inhibiting the function of PHD enzymes, they mimic the exposure to moderate hypoxia and stimulate the production of endogenous erythropoietin and very likely increase iron availability. Some data also suggest that their efficacy and, consequently, dose needs are less influenced by inflammation than ESAs. Overall, data from phases 2 and 3 clinical development showed efficacy in anemia correction and maintenance for all of the class molecules compared with placebo (superiority) or erythropoiesis-stimulating agents (noninferiority). Three molecules, roxadustat, vadadustat, and daprodustat, underwent extensive clinical investigation to assess their safety on hard cardiovascular end points, mortality, and special interest events (including cancer and thrombosis). Aside from vadadustat in the nondialysis population, at the prespecified primary analyses, all three molecules met the noninferiority margin for the risk of major cardiovascular events compared with erythropoiesis-stimulating agents or placebo. The reason for this discrepancy is difficult to explain. Other safety signals came from secondary analyses of some of the other randomized clinical trials, including a higher incidence of thrombosis. A more extensive clinical experience with post-marketing data on hard safety issues is needed to define better when and how to use HIF-PHD inhibitors compared with already available ESAs.