HIF prolyl hydroxylase inhibitors as treatments for renal anemia and other conditions

Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domaincontaining (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 oral administration and the simpler—and potentially cheaper— production. Importantly, inhibiting the PHD enzymes has 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. Maxwell, P. H. & Eckardt, K.-U. Nat. Rev. Nephrol. Pubished online 14 Dec 2015 P.H.M. Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, United Kingdom K-U.E. Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany Correspondence to: P.H.M. [email protected] Competing interests P.H.M. is the scientific founder, a shareholder and director of ReOx. K.-U.E. has received consultancy fees from companies that produce or distribute therapeutics for management of anaemia, including Akebia, Amgen, AstraZeneca, Johnson & Johnson, Roche, Sandoz, Takeda and Vifor. He has also received grant support from Bayer and Amgen for the German Chronic Kidney Disease (GCKD) study.