Hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors: ready for primetime?

Abstract

Purpose of reviewHypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors have recently been developed as a new treatment for anemia associated with chronic kidney disease (CKD). Several of these have been approved in Europe (roxadustat), China, and Japan, but none approved in the United States to date, although daprodustat has been submitted as a new drug application to the Food and Drug Administration. The aim of this review is to critically appraise the available data, particularly the most recent publications, and offer a personal viewpoint on whether or not these drugs are ready for primetime. Recent findingsThe efficacy of HIF prolyl hydroxylase inhibitors in improving CKD anemia and maintaining a higher hemoglobin is undisputed, but there remain some concerns about safety, particularly in the long term. Some of the safety concerns may result from an exaggerated pharmacological response, while other potential adverse effects could be due to transcriptional effects of these agents beyond genes involved in erythropoiesis. SummaryHIF prolyl hydroxylase inhibitors are already being used in clinical practice in several countries of the world, and ongoing research is being conducted to define the role of these drugs not only in the management of anemia but also beyond into other clinical settings.

Comparison of efficacy of roxadustat and erythropoietin for the treatment of renal anemia in patients with chronic kidney disease: a retrospective study

“…As a hypoxia-inducible factor prolyl hydroxylase inhibitor, roxadustat stabilizes hypoxia-inducible factors and stimulates the expression of the erythropoietin gene. It promotes increases in the concentrations of erythropoietin in certain organs, including the kidneys and liver, which is beneficial for maintaining Hb levels (26). In our study, the convenience of orally administered roxadustat resulted in high treatment compliance and led to more effective treatment than rhEPO for improving anemia.…”

Roxadustat, a HIF-PHD inhibitor with exploitable potential on diabetes-related complications

“…However, because the pathogenesis of DM is complex and the degree of hypoxia varies in different tissues, research on the treatment of diabetes and its complications by improving tissue hypoxia is still under further investigation. Roxadustat has been approved for the treatment of CKD anemia in Europe, China, and Japan, while other HIF-PH inhibitors have been approved in China and Japan alone (Macdougall, 2022). Comparing with other PHD inhibitors, roxadustat is generally well-tolerated and has been used in clinical practice.…”

Hypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease

“…Pharmacological manipulation of PHD-HIF axis has been quested for treating disorders related to local and systemic hypoxia. PHD inhibitors were developed for the treatment of chronic kidney disease (CKD)-related anemia ( Welden et al, 2017 ; Semenza, 2019 ; Wish et al, 2021 ; Macdougall, 2022 ). At least six PHD inhibitors roxadustat (FG-4592), daprodustat (GSK1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934), enarodustat (JTZ-951) and desidustat have been developed and the phase 3 clinical trials showed that their effects were non-inferior to current EPO-stimulating agents ( Sugahara et al, 2022 ).…”