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

Key Points

  • Erythropoietin production is controlled by hypoxia inducible factor (HIF); the prolyl hydroxylase domain-containing (PHD) enzymes regulate HIF and act as molecular oxygen sensors

  • Small-molecule inhibitors of the PHD enzymes increase erythropoietin production and are in clinical development for the treatment of renal anaemia

  • Advantages of PHD enzyme inhibitors over conventional erythropoiesis-stimulating agents (ESAs) include oral administration, lower production costs, product stability and low immunogenicity

  • PHD enzyme inhibitors have effects besides increasing production of erythropoietin. Some of these effects could be beneficial, including improvements in uptake and utilization of iron

  • The balance of risks and benefits in treating renal anaemia with PHD enzyme inhibitors is currently being addressed in randomized controlled trials

  • PHD inhibitors might be useful for therapeutic indications other than the management of renal anaemia

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.

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Figure 1: Control of erythropoietin production by the HIF pathway and PHD enzymes.
Figure 2: On-target and off-target effects of PHD enzyme inhibitors.
Figure 3: Chemical structures of small-molecule prolyl hydroxylase domain-containing enzyme inhibitors.

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Acknowledgements

The authors are grateful to Matthew Coleman (University of Birmingham, UK) for expert input into Supplementary Table 1, and to Akebia, GlaxoSmithKline, AstraZeneca and Bayer for providing information about ongoing clinical trials. Representatives of these companies had no influence on the content of this article. We recognize that not all scientific papers that relate to the topic of this Review could be included and apologize for the omission of any important contributions.

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Correspondence to Patrick H. Maxwell.

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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 Amgen and Bayer for the German Chronic Kidney Disease (GCKD) study.

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Supplementary Table 1

Human 2-oxoglutarate oxygenases and their reported associated substrates and human genetic diseases. (DOC 187 kb)

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Maxwell, P., Eckardt, KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol 12, 157–168 (2016). https://doi.org/10.1038/nrneph.2015.193

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