HIF prolyl-hydroxylase inhibitor explained

Imageclass:skin-invert-image
Atc Prefix:B03X
Mechanism Of Action:Enzyme inhibitor
Biological Target:HIF prolyl-hydroxylase

HIF prolyl-hydroxylase inhibitor should not be confused with Factor Inhibiting HIF Asparaginyl Hydroxylase Inhibitors.

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. 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).[2]

Therapeutic applications

Renal anemia

Several HIF-PHIs, including roxadustat, daprodustat, vadadustat, molidustat, and enarodustat, have been approved in various countries for the treatment of renal anemia. 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.[3] [4]

Other indications

Outside 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

In 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

As 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

The 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

See also

Notes and References

  1. Stoumpos S, Crowe K, Sarafidis P, Barratt J, Bolignano D, Del Vecchio L, Małyszko J, Więcek A, Ortiz A, Cozzolino M . 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 . September 2024 . 38573822 . 11427073 . 10.1093/ndt/gfae075 .
  2. Li J, Haase VH, Hao CM . Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia . Kidney Diseases . Basel, Switzerland . 9 . 1 . 1–11 . January 2023 . 36756084 . 9900466 . 10.1159/000527835 .
  3. Nakanishi T, Kuragano T . Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia . Clinical Kidney Journal . 17 . 3 . sfae051 . March 2024 . 38516524 . 10956400 . 10.1093/ckj/sfae051 .
  4. Haase VH . Hypoxia-inducible factor-prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease . Kidney International Supplements . 11 . 1 . 8–25 . April 2021 . 33777492 . 7983025 . 10.1016/j.kisu.2020.12.002 .
  5. Therapeutics . Akebia . 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) . 2023-02-15 . www.prnewswire.com . en.
  6. Web site: 2022-11-03 . Akebia Therapeutics, Inc. (AKBA) Q3 2022 Earnings Call Transcript Seeking Alpha . 2023-02-15 . seekingalpha.com . en.
  7. Web site: HIF-PHI-delity? As FDA spins new tune in CKD anemia with GSK nod, others in class may hope to play along . BioWorld . 2023-02-15 . en.
  8. Chen D, Niu Y, Liu F, Yang Y, Wang X, Li P, Chen X . Safety of HIF prolyl hydroxylase inhibitors for anemia in dialysis patients: a systematic review and network meta-analysis . Frontiers in Pharmacology . 14 . 1163908 . 2023 . 37292157 . 10244523 . 10.3389/fphar.2023.1163908 . free .
  9. Zheng Q, Wang Y, Yang H, Sun L, Zhang P, Zhang X, Guo J, Liu YN, Liu WJ . 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 . April 2023 . 36396085 . 10.1053/j.ajkd.2022.09.014 . 253570576 .
  10. Web site: vadadustat . 2023-02-15 . CSL Vifor . en-GB.
  11. Web site: Astellas Receives European Commission Approval for First-in-Class EVRENZO™ (roxadustat) for Adult Patients with Symptomatic Anemia of Chronic Kidney Disease . 2023-02-15 . Astellas Pharma US, Inc. News Room . en.

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