Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease

ABSTRACT

Introduction: In the last decade, concerns have been raised around the use of erythropoiesis-stimulating agents (ESAs) and intravenous iron in chronic kidney disease (CKD) patients, especially when given at high doses. Moreover, treatment with ESA is expensive.

Areas covered: We searched PubMed for original articles, reviews, and editorials having as a topic anemia, CKD, hypoxia inducible factor, hepcidin, iron, and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI). HIF-PHI are a new class of small molecules activating HIF-alfa isoforms (the main mediators of the effects of hypoxia on the body). This causes the secretion of endogenous erythropoietin and increased iron availability. Differing from ESA, HIF-PHI are administered orally. Preliminary data from phase-II clinical studies have shown their efficacy and safety in the short term.

Expert Opinion: HIF-PHI are a new promising class of drugs. The results of large, phase-III clinical studies are awaited to prove their efficacy and safety on cardiovascular events and cancer development in the long term. Their capability of penetrating the ESA market in the future will be influenced also by their selling price. The oral administration of HIF-PHI will be weighed to the ‘intra-lines’ infusion of ESA in hemodialysis or to the infrequent subcutaneous injections of long-acting ESA.

KEYWORDS:

• Anaemia
• chronic kidney disease
• erythropoietin
• hypoxia inducible factor
• hypoxia-inducible factor prolyl hydroxylase inhibitors

Article highlights box

• Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) mimic the effect of hypoxia by reducing the rate of the degradation of the HIF alfa subunit.

• HIF-PHI correct and maintain hemoglobin levels in CKD patients with much lower EPO peak levels compared to ESAs.

• Compared to ESAs, HIF-PHI increase iron absorption and improve iron utilization.

• HIF-PHI have the potential to correct anemia in inflamed patients who are hyporesponsive to ESA.

• Long-term data will prove whether HIF-PHI are safe in respect of cardiovascular complication, cancer development, and unexpected events.

This box summarizes key points contained in the article.

Disclosure statement

One of the peer reviewers on this manuscript has served on advisory boards for Fibrogen/AstraZeneca (roxadustat) and Akebia (vadadustat). Each of the reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Declaration of Interest

L Del Vecchio has participated on Advisory Boards for Astellas and Roche, and received speaker fees from Roche. F Locatelli is or was a senior member of an advisory board of Akebia, Amgen, Astellas and Vifor Fresenius medical care pharma and has received speaker fees by Amgen, Bayer, GSK, Roche and Vifor Fresenius medical care pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.