Hypoxia-inducible factor prolyl hydroxylase inhibitors: a paradigm shift for treatment of anemia in chronic kidney disease?

ABSTRACT

Introduction

The hypoxia-inducible factor prolyl hydroxylase (HIF-PH) pathway is responsible for regulating the biosynthesis of erythropoietin (EPO) and maintaining iron homeostasis. Investigational drugs that target the HIF-PH pathway are promising alternatives for treating anemia in Chronic Kidney Disease (CKD).

Areas covered

This review summarizes recent advances focused on the clinical development of HIF-PH inhibitors (HIF-PHIs) as potentially novel therapies in the treatment of anemia in CKD based on publications available on PubMed and restricted Google searches. We provide a comparison between HIF-PHIs regarding their pharmacokinetics, dosing regimens and safety concerns, structure-activity relationships, and alterations in key laboratory parameters observed in animal models and clinical trials.

Expert opinion

HIF-PHIs may be advantageous in some aspects compared to the conventional erythropoiesis-stimulating agents (ESAs). While ESAs could increase the risk of cardiovascular events due to rapid rises in ESA blood levels, HIF-PHIs have been reported to maintain EPO concentrations at levels that are closer to the normal physiological ranges. Although HIF-PHIs have been demonstrated to be relatively safe and effective in clinical trials, long-term safety data are needed in order to establish whether these therapeutic agents will lead to a major paradigm change in the treatment of anemia of CKD.

KEYWORDS:

• Anemia
• chronic kidney disease
• erythropoietin
• erythropoiesis stimulating agents
• hepcidin
• hepcidin antagonists
• hypoxia-inducible factor prolyl hydroxylase inhibitors
• iron

Article highlights

• Inhibition of the HIF-PH enzyme constitutes a promising approach for the development of novel therapeutic agents for treating anemia in patients with CKD.

• HIF-PHIs suppress hepcidin synthesis, leading to a decrease in hepcidin blood levels.

• HIF-PHIs increase iron bioavailability, correct and maintain hemoglobin and EPO blood concentrations, improving anemia in inflamed patients.

• Long-term safety data for HIF-PHIs will be crucial to further understand their potential adverse effects, such as malignancy and cardiovascular complications.

This box summarizes key points contained in the article.

Declaration of interest

RK Watt is a co-founder of Revitale Pharma that is advancing furin inhibitors as treatments for anemia. 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.

Reviewer disclosures

One of the reviewers on this manuscript serves on advisory boards for AstraZeneca and Akebia, and receives speakers bureau for AstraZeneca. Another reviewer serves on the Advisory board and receives speaker fees from Astellas, and is also on the advisory board for GSK and national leader of the ASCEND ND trial of GSK. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.