Tadao Akizawa1, Manabu Iwasaki2, Yusuke Yamaguchi3, Yoshikatsu Majikawa4, Michael Reusch5. 1. Department of Nephrology, Showa University School of Medicine, Tokyo, Japan akizawa@med.showa-u.ac.jp. 2. Department of Data Science, Yokohama City University, Yokohama, Japan. 3. Japan-Asia Data Science, Development, Astellas Pharma, Inc., Tokyo, Japan. 4. Japan-Asia Clinical Development 2, Development, Astellas Pharma, Inc., Tokyo, Japan. 5. Development Medical Science Urology and Nephrology, Astellas Pharma Europe B.V., Leiden, The Netherlands.
Abstract
BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia. METHODS: This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat's noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10-12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18-24 (∆Hb18-24). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10-12 g/dl (maintenance rate) at weeks 18-24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings. RESULTS: We randomly assigned 303 patients to roxadustat (n=151) or darbepoetin alfa (n=152). The difference between roxadustat and darbepoetin alfa in ∆Hb18-24 was -0.02 g/dl (95% confidence interval, -0.18 to 0.15), confirming roxadustat's noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18-24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18-24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups. CONCLUSIONS: Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).
BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia. METHODS: This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat's noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10-12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18-24 (∆Hb18-24). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10-12 g/dl (maintenance rate) at weeks 18-24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings. RESULTS: We randomly assigned 303 patients to roxadustat (n=151) or darbepoetin alfa (n=152). The difference between roxadustat and darbepoetin alfa in ∆Hb18-24 was -0.02 g/dl (95% confidence interval, -0.18 to 0.15), confirming roxadustat's noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18-24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18-24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups. CONCLUSIONS: Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).
Authors: Robert Provenzano; Anatole Besarab; Steven Wright; Sohan Dua; Steven Zeig; Peter Nguyen; Lona Poole; Khalil G Saikali; Gopal Saha; Stefan Hemmerich; Lynda Szczech; K H Peony Yu; Thomas B Neff Journal: Am J Kidney Dis Date: 2016-02-02 Impact factor: 8.860
Authors: Anatole Besarab; Elena Chernyavskaya; Igor Motylev; Evgeny Shutov; Lalathaksha M Kumbar; Konstantin Gurevich; Daniel Tak Mao Chan; Robert Leong; Lona Poole; Ming Zhong; Khalil G Saikali; Marietta Franco; Stefan Hemmerich; Kin-Hung Peony Yu; Thomas B Neff Journal: J Am Soc Nephrol Date: 2015-10-22 Impact factor: 10.121
Authors: Anatole Besarab; Robert Provenzano; Joachim Hertel; Raja Zabaneh; Stephen J Klaus; Tyson Lee; Robert Leong; Stefan Hemmerich; Kin-Hung Peony Yu; Thomas B Neff Journal: Nephrol Dial Transplant Date: 2015-08-03 Impact factor: 5.992
Authors: Steven Fishbane; Carol A Pollock; Mohamed El-Shahawy; Elizabeth T Escudero; Anjay Rastogi; Bui Pham Van; Lars Frison; Mark Houser; Maksym Pola; Dustin J Little; Nicolas Guzman; Pablo E Pergola Journal: J Am Soc Nephrol Date: 2022-04 Impact factor: 10.121
Authors: Daniel W Coyne; Simon D Roger; Sug Kyun Shin; Sung Gyun Kim; Andres A Cadena; Moustafa A Moustafa; Tak Mao Chan; Anatole Besarab; Willis Chou; Charles Bradley; Meraf Eyassu; Robert Leong; Tyson T Lee; Khalil G Saikali; Lynda Szczech; Kin-Hung P Yu Journal: Kidney Int Rep Date: 2020-12-05