open access

Vol 15, No 2 (2022)
Review paper
Get Citation

Roxadustat ― new therapeutic option for treatment of anemia in patients with chronic kidney disease

Andrzej Chamienia12, Alicja Dębska-Ślizień1
DOI: 10.5603/RDTF.2022.0010
·
Renal Disease and Transplantation Forum 2022;15(2):63-74.
Affiliations
  1. Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk
  2. Department of Medical and Pediatric Nursing, Institute of Nursing and Midwifery, Medical University of Gdańsk

open access

Vol 15, No 2 (2022)
Review articles

Abstract

Chronic kidney disease (CKD) is an increasingly common public health issue. It is estimated that it affects 8–16% of the global population. Anemia is a very common complication of chronic kidney disease, and its occurrence is associated with a reduced quality of life, increased morbidity, and mortality. The main causes of CKD anemia include erythropoietin (EPO) deficiency and iron deficiency (absolute and functional). In addition, the bone marrow response to EPO is reduced in patients with chronic inflammation, which is often present in patients with advanced stages of CKD and dialyzed patients. According to the current guidelines, the treatment of anemia in CKD involves recombinant erythropoiesis-stimulating agents (ESAs) along with iron supplementation. In some patients, intensive correction of anemia requiring high doses of ESA and intravenous iron may increase the risk of adverse events. The correction also requires injections, outpatient visits, and hospital stays, which is especially troublesome for pre-dialysis patients. The discovery of hypoxia-inducible factors (HIFs) responsible for stimulating cells to EPO synthesis and increased activity of oxygen-dependent genes enabled the development of new drugs, so-called HIF-PHI inhibitors (hypoxia-inducible factor-prolyl hydroxylase inhibitors, prolyl hydroxylase inhibitors). Those compounds reversibly inhibit the activityof the enzyme responsible for inactivating the HIF and thus increase endogenous EPO synthesis and affect iron metabolism. This discovery opened new
options for the treatment of anemia in CKD patients. Phase 2 and 3 clinical trials are conducted with several drugs: daprodustat (GSK-1278863), roxadustat (FG-4592), and wadadustat (AKB-6548). To date, only roxadustat has been approved for treatment of CKD-related anemia. Roxadustat (FG-4592) is a novel orally active, potent, and reversible inhibitor of prolyl hydroxylase (PHI), causing functional activation of target genes that encode proteins such as EPO, EPO receptor, heme biosynthesis enzymes, and proteins that enhance iron absorption and transport and thus promote formation and maturation of red blood cells (RBCs). This study aims to summarize the available results of studies on the use of roxadustat in

Abstract

Chronic kidney disease (CKD) is an increasingly common public health issue. It is estimated that it affects 8–16% of the global population. Anemia is a very common complication of chronic kidney disease, and its occurrence is associated with a reduced quality of life, increased morbidity, and mortality. The main causes of CKD anemia include erythropoietin (EPO) deficiency and iron deficiency (absolute and functional). In addition, the bone marrow response to EPO is reduced in patients with chronic inflammation, which is often present in patients with advanced stages of CKD and dialyzed patients. According to the current guidelines, the treatment of anemia in CKD involves recombinant erythropoiesis-stimulating agents (ESAs) along with iron supplementation. In some patients, intensive correction of anemia requiring high doses of ESA and intravenous iron may increase the risk of adverse events. The correction also requires injections, outpatient visits, and hospital stays, which is especially troublesome for pre-dialysis patients. The discovery of hypoxia-inducible factors (HIFs) responsible for stimulating cells to EPO synthesis and increased activity of oxygen-dependent genes enabled the development of new drugs, so-called HIF-PHI inhibitors (hypoxia-inducible factor-prolyl hydroxylase inhibitors, prolyl hydroxylase inhibitors). Those compounds reversibly inhibit the activityof the enzyme responsible for inactivating the HIF and thus increase endogenous EPO synthesis and affect iron metabolism. This discovery opened new
options for the treatment of anemia in CKD patients. Phase 2 and 3 clinical trials are conducted with several drugs: daprodustat (GSK-1278863), roxadustat (FG-4592), and wadadustat (AKB-6548). To date, only roxadustat has been approved for treatment of CKD-related anemia. Roxadustat (FG-4592) is a novel orally active, potent, and reversible inhibitor of prolyl hydroxylase (PHI), causing functional activation of target genes that encode proteins such as EPO, EPO receptor, heme biosynthesis enzymes, and proteins that enhance iron absorption and transport and thus promote formation and maturation of red blood cells (RBCs). This study aims to summarize the available results of studies on the use of roxadustat in

Get Citation

Keywords

chronic kidney disease, anemia, erythropoiesis stimulating agents, prolyl hydroxylase inhibitors

About this article
Title

Roxadustat ― new therapeutic option for treatment of anemia in patients with chronic kidney disease

Journal

Renal Disease and Transplantation Forum

Issue

Vol 15, No 2 (2022)

Article type

Review paper

Pages

63-74

Page views

340

Article views/downloads

66

DOI

10.5603/RDTF.2022.0010

Bibliographic record

Renal Disease and Transplantation Forum 2022;15(2):63-74.

Keywords

chronic kidney disease
anemia
erythropoiesis stimulating agents
prolyl hydroxylase inhibitors

Authors

Andrzej Chamienia
Alicja Dębska-Ślizień

References (46)
  1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013; 382(9888): 260–272.
  2. Dębska-Ślizień A, Rutkowski B, Jagodziński P, et al. Aktualny stan dializoterapii w Polsce — 2020. Nefrol Dial Pol. 2021; 25: 7–20.
  3. KDOQI, National Kidney Foundation. Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults. Am J Kidney Dis. 2006; 47(5 Suppl 3): S16–S85.
  4. Akizawa T, Okumura H, Alexandre AF, et al. Burden of anemia in chronic kidney disease patients in Japan: a literature review. Ther Apher Dial. 2018; 22(5): 444–456.
  5. Kidney Disease: Improving Global Outcomes Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012; 2(4): 279–335.
  6. Kliger AS, Foley RN, Goldfarb DS, et al. KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD. Am J Kidney Dis. 2013; 62(5): 849–859.
  7. Solomon SD, Uno H, Lewis EF, et al. Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010; 363(12): 1146–1155.
  8. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008; 74(6): 791–798.
  9. Kaplan J. Roxadustat and anemia of chronic kidney disease. N Engl J Med. 2019; 381(11): 1070–1072.
  10. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992; 12(12): 5447–5454.
  11. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292(5516): 468–472.
  12. Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001; 107(1): 43–54.
  13. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001; 13(2): 167–171.
  14. Lönnberg M, Garle M, Lönnberg L, et al. Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glycoform analysis. J Pharm Biomed Anal. 2013; 81–82: 187–192.
  15. Chin K, Yu X, Beleslin-Cokic B, et al. Production and processing of erythropoietin receptor transcripts in brain. Brain Res Mol Brain Res. 2000; 81(1-2): 29–42.
  16. Holdstock L, Meadowcroft AM, Maier R, et al. Four-week studies of oral hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol. 2016; 27(4): 1234–1244.
  17. Provenzano R, Besarab A, Wright S, et al. Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am J Kidney Dis. 2016; 67(6): 912–924.
  18. Provenzano R, Besarab A, Sun CH, et al. Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin J Am Soc Nephrol. 2016; 11(6): 982–991.
  19. Szczyra D, Śnit M, Grzeszczak W. Czy nowe doustne inhibitory hydroksylazy prolilowej to przyszłość w leczeniu niedokrwistości u chorych z przewlekłą chorobą nerek? Forum Nefrologiczne. 2020; 13(1): 1–13.
  20. Liu P, Wang L, DuBois BG, et al. Discovery of orally bioavailable and liver-targeted hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors for the treatment of anemia. ACS Med Chem Lett. 2018; 9(12): 1193–1198.
  21. Dhillon S. Roxadustat: first global approval. Drugs. 2019; 79(5): 563–572.
  22. Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a potential new treatment for anemia in patients with CKD . Am J Kidney Dis. 2017; 69(6): 815–826. Erratum in: Am J Kidney Dis. 2017; 69(6): 869.
  23. Besarab A, Provenzano R, Hertel J, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015; 30(10): 1665–1673.
  24. Chen N, Qian J, Chen J, et al. Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China. Nephrol Dial Transplant. 2017; 32(8): 1373–1386.
  25. Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019; 381(11): 1001–1010.
  26. Akizawa T, Yamaguchi Y, Otsuka T, et al. A phase 3, multicenter, randomized, two-arm, open-label study of intermittent oral dosing of roxadustat for the treatment of anemia in Japanese erythropoiesis-stimulating agent-naïve chronic kidney disease patients not on dialysis. Nephron. 2020; 144(8): 372–382.
  27. Akizawa T, Iwasaki M, Otsuka T, et al. Phase 3 study of roxadustat to treat anemia in non-dialysis-dependant CKD. Kidney Int Rep. 2021; 6(7): 1810–1828.
  28. Shutov E, Sułowicz W, Esposito C, et al. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS). Nephrol Dial Transplant. 2021; 36(9): 1629–1639.
  29. Coyne DW, Roger SD, Shin SK, et al. Roxadustat for CKD-related anemia in non-dialysis patients. Kidney Int Rep. 2021; 6(3): 624–635.
  30. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized phase 3 study. J Am Soc Nephrol. 2021; 32(3): 737–755.
  31. Barratt J, Andric B, Tataradze A, et al. Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant. 2021; 36(9): 1616–1628.
  32. Chen N, Hao C, Liu BC, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med. 2019; 381(11): 1011–1022.
  33. Akizawa T, Iwasaki M, Yamaguchi Y, et al. Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan. J Am Soc Nephrol. 2020; 31(7): 1628–1639.
  34. Akizawa T, Otsuka T, Reusch M, et al. Intermittent oral dosing of roxadustat in peritoneal dialysis chronic kidney disease patients with anemia: a randomized, phase 3, multicenter, open-label study. Ther Apher Dial. 2020; 24(2): 115–125.
  35. Hirai K, Nonaka H, Ueda M, et al. Effects of roxadustat on the anemia and iron metabolism of patients undergoing peritoneal dialysis. Front Med (Lausanne). 2021; 8: 667117.
  36. Charytan C, Manllo-Karim R, Martin ER, et al. A randomized trial of roxadustat in anemia of kidney failure: SIERRAS study. Kidney Int Rep. 2021; 6(7): 1829–1839.
  37. Csiky B, Schömig M, Esposito C, et al. Roxadustat for the maintenance treatment of anemia in patients with end-stage kidney disease on stable dialysis: a european phase 3, randomized, open-label, active-controlled study (PYRENEES). Adv Ther. 2021; 38(10): 5361–5380.
  38. Provenzano R, Shutov E, Eremeeva L, et al. Roxadustat for anemia in patients with end-stage renal disease incident to dialysis. Nephrol Dial Transplant. 2021; 36(9): 1717–1730.
  39. Provenzano R, Fishbane S, Szczech L, et al. Pooled analysis of roxadustat for anemia in patients with kidney failure incident to dialysis. Kidney Int Rep. 2021; 6(3): 613–623.
  40. Barratt J, Sulowicz W, Schömig M, et al. Efficacy and cardiovascular safety of roxadustat in dialysis-dependent chronic kidney disease: pooled analysis of four phase 3 studies. Adv Ther. 2021; 38(10): 5345–5360.
  41. Zheng Q, Yang H, Fu X, et al. The efficacy and safety of roxadustat for anemia in patients with chronic kidney disease: a meta-analysis. Nephrol Dial Transplant. 2021; 36(9): 1603–1615.
  42. Liu C, Fu Z, Jiang J, et al. Safety and efficacy of roxadustat for anemia in patients with chronic kidney disease: a meta-analysis and trial sequential analysis. Front Med (Lausanne). 2021; 8: 724456.
  43. Tang M, Zhu C, Yan T, et al. Safe and effective treatment for anemic patients with chronic kidney disease: an updated systematic review and meta-analysis on roxadustat. Front Pharmacol. 2021; 12: 658079.
  44. Locatelli F, Del Vecchio L. A new paradigm in treating patients with chronic kidney disease and anaemia after a journey lasting more than 35 years. Nephrol Dial Transplant. 2021; 36(9): 1559–1563.
  45. Babitt JL, Eisenga MF, Haase VH, et al. Conference Participants. Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2021; 99(6): 1280–1295.
  46. Charakterystyka Produktu Leczniczego (ChPL) Evrenzo. https://www.ema.europa.eu/documents/product-information/evrenzo-epar-product-information_pl.pdf (dostęp: 22.12.2021).

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.