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. 2021 Jul 5;7(6):494-502.
doi: 10.1159/000517053. eCollection 2021 Nov.

A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study

Tadao Akizawa  1 , Masaomi Nangaku  2 , Takuhiro Yamaguchi  3 , Ryosuke Koretomo  4 , Kazuo Maeda  4 , Yuya Miyazawa  4 , Hideki Hirakata  5
Affiliations

A Phase 3 Study of Enarodustat (JTZ-951) in Japanese Hemodialysis Patients for Treatment of Anemia in Chronic Kidney Disease: SYMPHONY HD Study

Tadao Akizawa et al. Kidney Dis (Basel). .

Abstract

Introduction: Enarodustat (JTZ-951) is a new oral hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). We conducted a phase 3 study to compare the efficacy and safety of enarodustat with darbepoetin alfa (DA) in Japanese anemic patients with CKD receiving maintenance hemodialysis.

Methods: Subjects receiving maintenance hemodialysis were randomly assigned at a 1:1 ratio to receive oral enarodustat once daily or intravenous DA every week for 24 weeks with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within a target range (≥10.0 to <12.0 g/dL). The primary efficacy endpoint was difference in mean Hb level between arms during the evaluation period defined as weeks 20-24 (noninferiority margin: -1.0 g/dL). Intravenous iron preparations were prohibited during the screening period and during weeks 0-4.

Results: The mean Hb level of each arm during the evaluation period was 10.73 g/dL (95% confidence interval [CI]: 10.56, 10.91) in the enarodustat arm and 10.85 g/dL (95% CI: 10.72, 10.98) in the DA arm. The difference in the mean Hb level between arms was -0.12 g/dL (95% CI: -0.33, 0.10), confirming the noninferiority of enarodustat to DA. The mean Hb level of each arm was maintained within the target range during the treatment period. Increased total iron-binding capacity and serum iron and decreased hepcidin were observed through week 4 in the enarodustat arm albeit after switching from erythropoiesis-stimulating agents. No apparent safety concerns of enarodustat were observed compared with DA.

Discussion/conclusion: Enarodustat was noninferior to DA for the treatment of anemia in CKD patients receiving maintenance hemodialysis and was generally well tolerated over 24 weeks.

Keywords: Anemia in chronic kidney disease; Enarodustat; Hypoxia-inducible factor-prolyl hydroxylase inhibitor; Iron utilization; Phase 3 study.

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Conflict of interest statement

T.A. reports personal fees from Japan Tobacco Inc. during the conduct of the study and personal fees from Astellas, Bayer Yakuhin Ltd., Kyowa Kirin Co. Ltd., Kissei Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Fuso Pharmaceutical Industries Ltd., Torii Pharmaceutical Co. Ltd., GlaxoSmithKline, Nipro Corporation, Otsuka Pharmaceutical, Sanwa Chemical, Chugai Pharmaceutical Co. Ltd., and Mitsubishi Tanabe Pharma Corporation outside of the submitted work. M.N. is an Editorial Board Member of the journal Kidney Diseases and reports grants and personal fees from Japan Tobacco Inc. during the conduct of the study and personal fees from Kyowa Kirin Co. Ltd., Astellas, Astra Zeneca, GlaxoSmithKline, Mitsubishi Tanabe Pharma Corporation, Akebia Therapeutics Inc., Bayer Yakuhin Ltd., and Torii Pharmaceutical Co. Ltd. and grants from Kyowa Kirin Co. Ltd., Astellas, Mitsubishi Tanabe Pharma Corporation, Bayer Yakuhin Ltd., and Torii Pharmaceutical Co. Ltd outside of the submitted work. T.Y. reports personal fees from Japan Tobacco Inc. during the conduct of the study and personal fees from Ono Pharmaceutical Co. Ltd., Kowa, Chugai Pharmaceutical Co. Ltd., TSUMURA&Co., CAC Croit Corporation, Kyowa Kirin Co. Ltd., Daiichi Sankyo, ASAHI INTECC, Asahi Kasei Corporation, Kaken Pharmaceutical, 3H Clinical Trial Co. Ltd., Welby, 3H Medi Solution, and Nipro Corporation and grants from Ono Pharmaceutical Co. Ltd., CAC Croit Corporation, Kyowa Kirin Co. Ltd., Daiichi Sankyo, 3H Clinical Trial Co. Ltd., AC Medical, A2 Healthcare, Facet Biotech, Japan Media Corporation, Luminary Medical, Medidata Solutions Inc., Senju Pharmaceutical, Otsuka Pharmaceutical, Eisai, FMD K&L Japan, Intellim, Welby, 3H Medi Solution, Nipro Corporation, Hemp Kitchen, NOBORI, Puravida Technologies LLC., and Medrio Inc. outside of the submitted work. H.H. reports personal fees from Japan Tobacco Inc. during the conduct of the study and personal fees from Kyowa Kirin Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Torii Pharmaceutical Co. Ltd. outside of the submitted work. R.K., K.M., and Y.M. are employees of Japan Tobacco Inc.

Figures

Fig. 1
Fig. 1
Hb levels over time and mean dose of enarodustat and DA (FAS). Each point indicates the mean Hb level in each arm (closed circles: enarodustat arm; open circles: DA arm), and bars indicate the 95% CI. The table shows mean dose of enarodustat and DA in each period. Hb, hemoglobin; EOT, end of treatment; CI, confidence interval; DA, darbepoetin alfa; F-up, follow-up; FAS, full analysis set.
Fig. 2
Fig. 2
Changes in iron-related parameters (FAS). Each point indicates the median value in each arm (closed circles: enarodustat arm; open circles: DA arm), and bars indicate the interquartile range. Intergroup comparisons of changes at week 4 between arms were performed for the post hoc analysis using the Wilcoxon rank sum test (significance level: 5%, 2-sided). *p < 0.05; **p < 0.0001. DA, darbepoetin alfa; TIBC, total iron-binding capacity; TSAT, transferrin saturation; F-up, follow-up; FAS, full analysis set.
See this image and copyright information in PMC

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