HIF prolyl-hydroxylase inhibitor
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a novel class of oral medications developed for the treatment of anemia in chronic kidney disease (CKD). These drugs work by inhibiting hypoxia-inducible factor-proline dioxygenase (HIF prolyl-hydroxylase), which are responsible for the degradation of hypoxia-inducible factor (HIF) under normal oxygen conditions.[1] By stabilizing HIF, these inhibitors mimic the body's natural response to hypoxia, leading to increased endogenous erythropoietin production and improved iron metabolism.[2] HIF-PHIs have shown efficacy in correcting and maintaining hemoglobin levels in both dialysis-dependent and non-dialysis-dependent CKD patients, offering an alternative to traditional erythropoiesis-stimulating agents (ESAs).[1][3]
| HIF prolyl-hydroxylase inhibitor | |
|---|---|
| Drug class | |
 Roxadustat, the first marketed HIF prolyl-hydroxylase inhibitor | |
| Class identifiers | |
| ATC code | B03X |
| Mechanism of action | Enzyme inhibitor |
| Biological target | HIF prolyl-hydroxylase |
| Legal status | |
| In Wikidata | |
Therapeutic applications
editRenal anemia
editSeveral HIF-PHIs, including roxadustat, daprodustat, vadadustat, molidustat, and enarodustat, have been approved in various countries for the treatment of renal anemia.[3][4] While these drugs have demonstrated promising results in clinical trials, ongoing research is focused on evaluating their long-term safety profile, particularly regarding cardiovascular outcomes, thromboembolic events, and potential effects on tumor growth.[1][4][2]
Other indications
editOutside of chronic kidney disease, Akebia Therapeutics has reported preliminary findings from its phase II study on Vadadustat for acute respiratory distress syndrome (ARDS) in COVID-19 patients.[5] Based on these results, Akebia Therapeutics plans to proceed with a phase III study targeting a broader ARDS patient population.[6]
Regulatory status
editIn Japan, all three drugs are available for clinical use. In the European Union, Vadadustat and Daprodustat are currently under regulatory review for potential approval as of 2023. In early 2023, the U.S. FDA approved Daprodustat following a positive advisory committee decision, which supported its favorable benefit-risk profile. Vadadustat, however, is awaiting a decision on a formal dispute resolution appeal, especially in light of the recent FDA approval for Daprodustat.[7]
Clinical development
editAs of 2023, Vadadustat, Daprodustat, and Roxadustat are the most extensively studied HIF-PHIs, with a significant volume of phase III and phase IV data supporting their use in treating chronic kidney disease.[8][9]
Commercial development
editThe rights to Vadadustat are held by Akebia Therapeutics in partnership with CSL Vifor. Roxadustat is owned by Fibrogen in partnership with Astellas, while Daprodustat has been developed internally by GSK.[10][11]
Examples
edit- Daprodustat
- Desidustat
- Enarodustat
- Molidustat
- Roxadustat (marketed in China)
- Vadadustat
See also
editReferences
edit- ^ a b c Stoumpos S, Crowe K, Sarafidis P, Barratt J, Bolignano D, Del Vecchio L, et al. (September 2024). "Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a clinical practice document by the European Renal Best Practice board of the European Renal Association". Nephrology, Dialysis, Transplantation. 39 (10): 1710–1730. doi:10.1093/ndt/gfae075. PMC 11427073. PMID 38573822.
- ^ a b Haase VH (April 2021). "Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease". Kidney International Supplements. 11 (1): 8–25. doi:10.1016/j.kisu.2020.12.002. PMC 7983025. PMID 33777492.
- ^ a b Li J, Haase VH, Hao CM (January 2023). "Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia". Kidney Diseases. 9 (1). Basel, Switzerland: 1–11. doi:10.1159/000527835. PMC 9900466. PMID 36756084.
- ^ a b Nakanishi T, Kuragano T (March 2024). "Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia". Clinical Kidney Journal. 17 (3): sfae051. doi:10.1093/ckj/sfae051. PMC 10956400. PMID 38516524.
- ^ Therapeutics A. "Akebia Therapeutics Announces Initial Findings from Investigator-Sponsored Clinical Study Evaluating Vadadustat for the Prevention and Treatment of Acute Respiratory Distress Syndrome (ARDS) in Subjects with COVID-19 and Hypoxemia (VSTAT)". www.prnewswire.com (Press release). Retrieved 2023-02-15.
- ^ "Akebia Therapeutics, Inc. (AKBA) Q3 2022 Earnings Call Transcript | Seeking Alpha". seekingalpha.com. 2022-11-03. Retrieved 2023-02-15.
- ^ "HIF-PHI-delity? As FDA spins new tune in CKD anemia with GSK nod, others in class may hope to play along". BioWorld. Retrieved 2023-02-15.
- ^ Chen D, Niu Y, Liu F, Yang Y, Wang X, Li P, et al. (2023). "Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis". Frontiers in Pharmacology. 14: 1163908. doi:10.3389/fphar.2023.1163908. PMC 10244523. PMID 37292157.
- ^ Zheng Q, Wang Y, Yang H, Sun L, Zhang P, Zhang X, et al. (April 2023). "Cardiac and Kidney Adverse Effects of HIF Prolyl-Hydroxylase Inhibitors for Anemia in Patients With CKD Not Receiving Dialysis: A Systematic Review and Meta-analysis". American Journal of Kidney Diseases. 81 (4): 434–445.e1. doi:10.1053/j.ajkd.2022.09.014. PMID 36396085. S2CID 253570576.
- ^ "vadadustat". CSL Vifor. Retrieved 2023-02-15.
- ^ "Astellas Receives European Commission Approval for First-in-Class EVRENZO™ (roxadustat) for Adult Patients with Symptomatic Anemia of Chronic Kidney Disease". Astellas Pharma US, Inc. | News Room. Retrieved 2023-02-15.
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