Skip to main content

Roxadustat: First Global Approval

Abstract

Roxadustat (Ai Rui Zhuo® in China) is an orally administered, small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that is being developed by FibroGen, in collaboration with Astellas and AstraZeneca, for the treatment of anaemia in patients with dialysis-dependent chronic kidney disease (CKD), non-dialysis-dependent CKD and in patients with myelodysplastic syndromes. The drug reversibly binds to and inhibits HIF-prolyl hydroxylase enzymes that are responsible for the degradation of transcription factors in the HIF family under normal oxygen conditions. Inhibition of these enzymes reduces HIF breakdown and promotes HIF activity, leading to an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. It also reduces the expression of the peptide hormone hepcidin, improves iron availability and increases haemoglobin levels. HIF regulates the expression of genes in response to reduced oxygen levels, including genes required for erythropoiesis and iron metabolism. Roxadustat is approved in China and is under regulatory review in Japan for the treatment of anaemia in patients with dialysis-dependent CKD. Studies are underway to investigate long-term cardiovascular outcomes with roxadustat versus placebo (for non-dialysis-dependent CKD) or standard of care (for dialysis-dependent CKD). This article summarizes the milestones in the development of roxadustat leading to this first approval.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Becker K, Saad M. A new approach to the management of anemia in CKD patients: a review on roxadustat. Adv Ther. 2017;34(4):848–53.

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Locatelli F, Fishbane S, Block GA, et al. Targeting hypoxia-inducible factors for the treatment of anemia in chronic kidney disease patients. Am J Nephrol. 2017;45(3):187–99.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    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):815–26.

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Fishbane S, Spinowitz B. Update on anemia in ESRD and earlier stages of CKD: core curriculum 2018. Am J Kidney Dis. 2018;71(3):423–35.

    Article  PubMed  Google Scholar 

  5. 5.

    Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017;21(Suppl 1):S110–24.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    FibroGen. FibroGen announces approval of roxadustat in China for the treatment of anemia in chronic kidney disease patients on dialysis [media release]. 17 Dec 2018. http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=2380952.

  7. 7.

    FibroGen. FibroGen enters agreement with Yamanouchi to license erythropoietic small molecule in development for the treatment of anemia [media release]. 24 Sep 2004. http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=1984318.

  8. 8.

    FibroGen. FibroGen licenses oral HIF-PH inhibitors, including FG-2216 and FG-4592, to Astellas for the treatment of anemia in Europe and other regions; FibroGen positioned to develop first oral anemia therapy for North America [media release]. 28 Apr 2006. http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=1984254.

  9. 9.

    FibroGen. FibroGen announces initiation of phase 2b studies of FG-4592, an oral HIF prolyl hydroxylase inhibitor, for treatment of anemia in chronic kidney disease [media release]. 17 Mar 2011. http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=1983440.

  10. 10.

    AstraZeneca. AstraZeneca and FibroGen collaborate to develop and commercialize FG-4592, a treatment for anemia in chronic kidney disease and end-stage renal disease [media release]. 31 Jul 2013. https://www.astrazeneca.com/media-centre/press-releases/2013/astrazeneca-fibrogen-fg4592-anaemia-treatment-chronic-kidney-disease-renal-disease-31072013.html#.

  11. 11.

    FibroGen. FibroGen announces receipt of $62 million license payment from AstraZeneca [media release]. 8 Jul 2016. http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=2182906.

  12. 12.

    FibroGen. FibroGen announces receipt of $120 million license payment from AstraZeneca [media release]. 29 Jun 2015. http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=2063398.

  13. 13.

    FibroGen. FibroGen’s roxadustat (FG-4592) meets primary endpoints in two phase 3 anemia studies in China [media release]. 30 Jan 2017. http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle&ID=2240513.

  14. 14.

    FibroGen Inc. SEC Filings: form 10-K. 2018. http://phx.corporate-ir.net/phoenix.zhtml?c=253783&p=irol-SECText&TEXT=aHR0cDovL2FwaS50ZW5rd2l6YXJkLmNvbS9maWxpbmcueG1sP2lwYWdlPTEyMDg4MDE4JkRTRVE9MCZTRVE9MCZTUURFU0M9U0VDVElPTl9FTlRJUkUmc3Vic2lkPTU3. Accessed 2018.

  15. 15.

    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):1665–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Haase VH. Hypoxic regulation of erythropoiesis and iron metabolism. Am J Physiol Renal Physiol. 2010;299(1):F1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    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):1373–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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):982–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Yu KH, Chou J, Klaus S, et al. Comparable doses of FG-4592 have similar PK/PD in healthy Caucasian and Japanese subjects (abstract no. MP204). Nephrol Dial Transplant. 2013;28(Suppl 1):i362.

  20. 20.

    Chen X, Zheng X, Jiang J, et al. FG4592, a novel inhibitor of the prolyl hydroxylase of hypoxia-inducible factor (HIF-PH) elicited linear-exponential dose-response profile on plasma erythropoietin (EPO) levels (abstract no. P413). Haematologica. 2013;98(Suppl 1):175–6.

  21. 21.

    Shibata T, Nomura Y, Takada A, et al. Evaluation of food and spherical carbon adsorbent effects on the pharmacokinetics of roxadustat in healthy nonelderly adult male Japanese subjects. Clin Pharmacol Drug Dev. 2018. https://doi.org/10.1002/cpdd.597.

  22. 22.

    Groenendaal-van de Meent D, Adel MD, Noukens J, et al. Effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. Clin Drug Investig. 2016;36(9):743–51.

  23. 23.

    Groenendaal-van de Meent D, den Adel M, van Dijk J, et al. Effect of multiple doses of omeprazole on the pharmacokinetics, safety, and tolerability of roxadustat in healthy subjects. Eur J Drug Metab Pharmacokinet. 2018. https://doi.org/10.1007/s13318-018-0480-z.

  24. 24.

    Shibata T, Nomura Y, Takada A, et al. Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non-elderly healthy adult male subjects. J Clin Pharm Ther. 2018;43(5):633–9.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Groenendaal-van de Meent D, den Adel M, Rijnders S, et al. The hypoxia-inducible factor prolyl-hydroxylase inhibitor roxadustat (FG-4592) and warfarin in healthy volunteers: a pharmacokinetic and pharmacodynamic drug-drug interaction study. Clin Ther. 2016;38(4):918–28.

  26. 26.

    FibroGen. FibroGen announces positive topline results from three global phase 3 trials of roxadustat for treatment of anemia in patients with chronic kidney disease: primary efficacy endpoints met in all three studies, non-dialysis, incident dialysis, and stable dialysis studies [media release]. 20 Dec 2018. http://investor.fibrogen.com/phoenix.zhtml?c=253783&p=irol-newsArticle_print&ID=2381297.

  27. 27.

    Chen N, Hao C-M, Liu B-C, et al. A phase 3, randomized, open-label, active-controlled study of efficacy and safety of roxadustat for treatment of anemia in subjects with CKD on dialysis (abstract no. TH-PO1152). J Am Soc Nephrol. 2018;29(Suppl):B5.

  28. 28.

    Akizawa T, Iwasaki M, Yamaguchi Y, et al. Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) conversion study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan (abstract no. TH-PO1151). J Am Soc Nephrol. 2018;29(Suppl):B4–B5.

  29. 29.

    Akizawa T, Otsuka T, Reusch M, et al. Phase 3, multicenter, open-label study of intermittent oral roxadustat in peritoneal dialysis CKD patients with anemia (abstract no. SA-OR075). J Am Soc Nephrol. 2018;29(Suppl):99.

  30. 30.

    AstraZeneca. Phase III OLYMPUS and ROCKIES trials for roxadustat met their primary endpoints in chronic kidney disease patients with anaemia [media release]. 2018. https://www.astrazeneca.com/media-centre/press-releases/2018/phase-iii-olympus-and-rockies-trials-for-roxadustat-met-their-primary-endpoints-in-chronic-kidney-disease-patients-with-anaemia20122018.html.

  31. 31.

    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):912–24.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Besarab A, Chernyavskaya E, Motylev I, et al. Roxadustat (FG-4592): correction of anemia in incident dialysis patients. J Am Soc Nephrol. 2016;27(4):1225–33.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Astellas Pharma. Astellas announces positive topline results for global phase 3 trial of roxadustat in chronic kidney disease (CKD) patients with anemia not on dialysis [media release]. 20 Sep 2018. https://www.astellas.com/system/files/news/2018-09/180920_eg.pdf.

  34. 34.

    Chen N, Hao C-M, Peng X, et al. A phase 3, randomized, double-blind, placebo-controlled study of efficacy and safety of roxadustat (FG-4592) for treatment of anemia in subjects with CKD not on dialysis (abstract no. TH-PO1153). J Am Soc Nephrol. 2018;29(Suppl.):B5.

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Sohita Dhillon.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Conflict of interest

During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Sohita Dhillon is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch and beyond.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dhillon, S. Roxadustat: First Global Approval. Drugs 79, 563–572 (2019). https://doi.org/10.1007/s40265-019-01077-1

Download citation