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

Abstract

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.

Keywords: HIF-PHD inhibitors; anemia; chronic inflammation; chronic kidney disease; dialysis; erythropoiesis-stimulating agents; erythropoietin; hemoglobin; hypoxia inducible factor; major cardiovascular events.

Figure 1.

Mechanisms of action of HIF-PHI. PHD enzymes reduce their activity because of hypoxia, iron deficiency, or during treatment with HIF-PHI. Consequently, HIFα half-life increases and becomes available for entering the nucleus and heterodimerizing with the HIF1β subunit. The obtained transcription factor activates or suppresses the activity of several genes that are summarized in the bottom part of the figure. In particular, HIF activation increases iron availability and stimulates erythropoietin production, leading to increased erythropoiesis. It is also possible that the action of HIF activation on inflammation could reduce hepcidin levels and increase the erythropoietic response.

Figure 2.

Mean Hb changes from baseline in nondialysis and dialysis patients. (A) Nondialysis patients. Mean Hb changes from baseline in the main phase 3 randomized clinical trials testing HIF-PHI compared with placebo or darbepoetin alfa. (B) Dialysis patients. Mean Hb changes from baseline in the main phase 3 randomized clinical trials testing HIF-PHI compared with ESA.

Figure 3.

Graphical representation of the Hb target and noninferiority margins used during the main RCT testing HIF-PHI in nondialysis and dialysis patients. RCTs testing roxadustat used a Hb target of 10–12 g/dl worldwide. RCTs with vadadustat had a lower Hb target for the United States than other countries. Daprodustat trials had the same Hb target worldwide (10–11 g/dl). Noninferiority margins were 1.2–1.25 for daprodustat, 1.25 for vadadustat, and 1.3 for roxadustat. MACE, major adverse cardiovascular events.