Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects

PLoS One. 2014 Nov 13;9(11):e111838. doi: 10.1371/journal.pone.0111838. eCollection 2014.

Abstract

Oxygen sensing by hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) is the dominant regulatory mechanism of erythropoietin (EPO) expression. In chronic kidney disease (CKD), impaired EPO expression causes anemia, which can be treated by supplementation with recombinant human EPO (rhEPO). However, treatment can result in rhEPO levels greatly exceeding the normal physiological range for endogenous EPO, and there is evidence that this contributes to hypertension in patients with CKD. Mimicking hypoxia by inhibiting HIF-PHs, thereby stabilizing HIF, is a novel treatment concept for restoring endogenous EPO production. HIF stabilization by oral administration of the HIF-PH inhibitor BAY 85-3934 (molidustat) resulted in dose-dependent production of EPO in healthy Wistar rats and cynomolgus monkeys. In repeat oral dosing of BAY 85-3934, hemoglobin levels were increased compared with animals that received vehicle, while endogenous EPO remained within the normal physiological range. BAY 85-3934 therapy was also effective in the treatment of renal anemia in rats with impaired kidney function and, unlike treatment with rhEPO, resulted in normalization of hypertensive blood pressure in a rat model of CKD. Notably, unlike treatment with the antihypertensive enalapril, the blood pressure normalization was achieved without a compensatory activation of the renin-angiotensin system. Thus, BAY 85-3934 may provide an approach to the treatment of anemia in patients with CKD, without the increased risk of adverse cardiovascular effects seen for patients treated with rhEPO. Clinical studies are ongoing to investigate the effects of BAY 85-3934 therapy in patients with renal anemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / drug therapy*
  • Anemia / etiology
  • Animals
  • Erythropoietin / biosynthesis*
  • Erythropoietin / genetics
  • Female
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Macaca fascicularis
  • Male
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Rats
  • Rats, Wistar
  • Renal Insufficiency, Chronic / complications
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use
  • Up-Regulation

Substances

  • Pyrazoles
  • Triazoles
  • Erythropoietin
  • molidustat
  • Hypoxia-Inducible Factor-Proline Dioxygenases

Grant support

This study was funded by Bayer Pharma AG. All the authors are employees of Bayer Pharma AG. The funder provided support in the form of salaries for all authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the authors are articulated in the ‘author contributions’ section.