HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond

Abstract

Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury.

Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease

“…HIF stabilization via PHD inhibition promotes erythropoiesis by stimulating endogenous EPO secretion and improving iron availability [20]. Prior studies of vadadustat in healthy volunteers and CKD patients demonstrated modest increases in endogenous EPO levels - which were similar to those observed following exposure to moderate altitude [21] - as well as preserved physiologic diurnal variation of serum EPO levels [17,18].…”

Time-dependent inhibition of PHD2

“…The modulation of the activity of these enzymes could be beneficial for the treatment of a variety of diseases, therefore, a large number of PHD2 inhibitors have been developed and are now in late stage clinical trials for the treatment of anemia and chronic kidney diseases [8][9][10][11][12][13]. Several companies have reported PHD inhibitors in clinical development for the treatment of ischemia and anemia associated with chronic renal disease.…”

Anaemia of Chronic Kidney Disease: What We Know Now

“…Advantages of this new class of drug include oral administration, low immunogenicity, product stability and possibly lower costs as well as potential cardiovascular benefits (84).…”