Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients - PubMed (original) (raw)
Clinical Trial
. 2016 Apr;27(4):1225-33.
doi: 10.1681/ASN.2015030241. Epub 2015 Oct 22.
Elena Chernyavskaya 2, Igor Motylev 3, Evgeny Shutov 4, Lalathaksha M Kumbar 5, Konstantin Gurevich 6, Daniel Tak Mao Chan 7, Robert Leong 8, Lona Poole 8, Ming Zhong 8, Khalil G Saikali 8, Marietta Franco 8, Stefan Hemmerich 8, Kin-Hung Peony Yu 8, Thomas B Neff 8
Affiliations
- PMID: 26494833
- PMCID: PMC4814189
- DOI: 10.1681/ASN.2015030241
Clinical Trial
Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients
Anatole Besarab et al. J Am Soc Nephrol. 2016 Apr.
Abstract
Safety concerns with erythropoietin analogues and intravenous (IV) iron for treatment of anemia in CKD necessitate development of safer therapies. Roxadustat (FG-4592) is an orally bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. We performed an open-label, randomized hemoglobin (Hb) correction study in anemic (Hb≤10.0 g/dl) patients incident to hemodialysis (HD) or peritoneal dialysis (PD). Sixty patients received no iron, oral iron, or IV iron while treated with roxadustat for 12 weeks. Mean±SD baseline Hb was 8.3±1.0 g/dl in enrolled patients. Roxadustat at titrated doses increased mean Hb by ≥2.0 g/dl within 7 weeks regardless of baseline iron repletion status, C-reactive protein level, iron regimen, or dialysis modality. Mean±SEM maximal change in Hb from baseline (ΔHb(max)), the primary endpoint, was 3.1±0.2 g/dl over 12 weeks in efficacy-evaluable patients (n=55). In groups receiving oral or IV iron, ΔHb(max) was similar and larger than in the no-iron group. Hb response (increase in Hb of ≥1.0 g/dl from baseline) was achieved in 96% of efficacy-evaluable patients. Mean serum hepcidin decreased significantly 4 weeks into study: by 80% in HD patients receiving no iron (n=22), 52% in HD and PD patients receiving oral iron (n=21), and 41% in HD patients receiving IV iron (n=9). In summary, roxadustat was well tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron repletion status or C-reactive protein level and with oral or IV iron supplementation; it also reduced serum hepcidin levels.
Keywords: anemia; chronic kidney disease; dialysis; erythropoietin.
Copyright © 2016 by the American Society of Nephrology.
Figures
Figure 1.
Patient disposition. Screened refers to the inclusion and exclusion criteria listed under "Selection of Study Population" in the
Supplemental Material
. FU, follow-up period. *The adverse events were dizziness in the no-iron cohorts and worsening gastritis in the IV iron cohort. ^Recovery of renal function. Most study patients (54 of 60 [90.0%]) were enrolled in Russia. The most common causes of renal failure (all patients combined) were unspecified GN (41.7%), pyelonephritis (21.7%), hypertensive nephropathy (18.3%), and diabetic nephropathy (15.0%).
Figure 2.
Mean hemoglobin levels over time are similar through 7 weeks for all treatment groups and thereafter lower for the no-iron vs oral or IV iron groups. Data are for the EE population using last-observation-carried-forward imputation for missing data and are expressed as the mean±SEM Hb value at each time point. Week 0 (baseline) is the mean of three predosing Hb values. *P<0.05 in comparisons between no-iron cohort to the pooled iron cohorts based on the repeated-measures analysis of covariance model with baseline Hb and iron repletion status as covariates, using all observed data collected during treatment.
Figure 3.
Cumulative Hb responses are similar among the cohorts. Data are for the EE population. Hb response was defined as the first Hb increase from baseline of ≥1.0 g/dl. Median time to first response was 3.0 weeks in all cohorts.
Figure 4.
_Δ_Hbmax during last 10 weeks of treatment (g/dl) is independent of baseline CRP level. Data are for the EE population. Baseline CRP was defined as the last value before the first dose administration. LR, linear regression on log(CRP) with adjustment of treatment cohort, baseline Hb, and baseline iron repletion. _Δ_Hbmax versus log(baseline CRP): regression slope on log(CRP) = −0.31 (_P_=0.30). All patients with CRP greater than the upper limit of normal (ULN=5 g/ml) responded to treatment.
Figure 5.
Weekly roxadustat dose during the last 2 weeks of the treatment period is independent of baseline CRP level. Data are for the EE population. Baseline CRP was defined as the last value before the first dose administration. LR, linear regression on log(CRP) with adjustment of treatment cohort, baseline Hb, and baseline iron repletion. Maintenance dose was defined as total dose during last 2 weeks of treatment. Maintenance dose versus log (baseline CRP): regression slope on log(baseline CRP) = −0.43 (_P_=0.38). ULN, upper limit of normal (5 ng/ml).
Comment in
- The Dawning of a New Day in CKD Anemia Care?
Lenihan CR, Winkelmayer WC. Lenihan CR, et al. J Am Soc Nephrol. 2016 Apr;27(4):968-70. doi: 10.1681/ASN.2015091009. Epub 2015 Oct 22. J Am Soc Nephrol. 2016. PMID: 26494832 Free PMC article. No abstract available.
Similar articles
- 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.
Provenzano R, Besarab A, Wright S, Dua S, Zeig S, Nguyen P, Poole L, Saikali KG, Saha G, Hemmerich S, Szczech L, Yu KH, Neff TB. Provenzano R, et al. Am J Kidney Dis. 2016 Jun;67(6):912-24. doi: 10.1053/j.ajkd.2015.12.020. Epub 2016 Feb 2. Am J Kidney Dis. 2016. PMID: 26846333 Clinical Trial. - Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD.
Provenzano R, Besarab A, Sun CH, Diamond SA, Durham JH, Cangiano JL, Aiello JR, Novak JE, Lee T, Leong R, Roberts BK, Saikali KG, Hemmerich S, Szczech LA, Yu KP, Neff TB. Provenzano R, et al. Clin J Am Soc Nephrol. 2016 Jun 6;11(6):982-991. doi: 10.2215/CJN.06890615. Epub 2016 Apr 19. Clin J Am Soc Nephrol. 2016. PMID: 27094610 Free PMC article. Clinical Trial. - Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients.
Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, Leong R, Hemmerich S, Yu KH, Neff TB. Besarab A, et al. Nephrol Dial Transplant. 2015 Oct;30(10):1665-73. doi: 10.1093/ndt/gfv302. Epub 2015 Aug 3. Nephrol Dial Transplant. 2015. PMID: 26238121 Free PMC article. Clinical Trial. - Roxadustat: First Global Approval.
Dhillon S. Dhillon S. Drugs. 2019 Apr;79(5):563-572. doi: 10.1007/s40265-019-01077-1. Drugs. 2019. PMID: 30805897 Review. - Efficacy and safety of roxadustat for anaemia in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients: A systematic review and meta-analysis.
Zheng L, Tian J, Liu D, Zhao Y, Fang X, Zhang Y, Liu Y. Zheng L, et al. Br J Clin Pharmacol. 2022 Mar;88(3):919-932. doi: 10.1111/bcp.15055. Epub 2021 Sep 30. Br J Clin Pharmacol. 2022. PMID: 34428860 Review.
Cited by
- Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors as a New Treatment Option for Anemia in Chronic Kidney Disease.
Bartnicki P. Bartnicki P. Biomedicines. 2024 Aug 18;12(8):1884. doi: 10.3390/biomedicines12081884. Biomedicines. 2024. PMID: 39200348 Free PMC article. Review. - Effects of roxadustat on thyroid hormone levels and blood lipid metabolism in patients undergoing hemodialysis: a retrospective study.
Li N, Cui W, Mu D, Shi X, Gao L, Liu S, Wang H, Jiang C, Hu Y. Li N, et al. Int J Med Sci. 2024 Jul 9;21(10):1806-1813. doi: 10.7150/ijms.97599. eCollection 2024. Int J Med Sci. 2024. PMID: 39113891 Free PMC article. - A preliminary study of roxadustat in the treatment of aplastic anemia patients with inadequate erythroid responses.
Shi Y, Zhao Y, Liang W, Zhang B, Kang R, Yang W, Zhao X, Zhang F. Shi Y, et al. Ann Hematol. 2024 Aug;103(8):2757-2763. doi: 10.1007/s00277-024-05799-5. Epub 2024 May 22. Ann Hematol. 2024. PMID: 38775949 Free PMC article. Clinical Trial. - A retrospective study on the efficacy of Roxadustat in peritoneal dialysis patients with erythropoietin hyporesponsiveness.
Liu J, Li S, Yang F, Li T, Li R, Waheed Y, Meng C, Li S, Liu K, Tong Y, Xu H, Tian C, Zhou X. Liu J, et al. Korean J Intern Med. 2024 May;39(3):488-500. doi: 10.3904/kjim.2023.520. Epub 2024 Apr 23. Korean J Intern Med. 2024. PMID: 38649158 Free PMC article. - From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease.
Yeh TH, Tu KC, Wang HY, Chen JY. Yeh TH, et al. Int J Mol Sci. 2024 Feb 1;25(3):1755. doi: 10.3390/ijms25031755. Int J Mol Sci. 2024. PMID: 38339031 Free PMC article. Review.
References
- Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351: 1296–1305, 2004 - PubMed
- U.S. Renal Data System: 2013 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. Available at http://www.usrds.org/atlas.htm. Accessed October 1, 2014
- Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D, CHOIR Investigators : Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355: 2085–2098, 2006 - PubMed
- KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis 50: 471–530, 2007 - PubMed
- Arbor Research Collaborative For Health. DOPPS Practice Monitor: 2013 Annual Report of the Dialysis Outcomes and Practice Patterns Study: Hemodialysis Data 1997-2012. Available at http://www.dopps.org/annual report/
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials