Efficacy and safety of vadadustat compared with darbepoetin alfa in Japanese anemic patients on hemodialysis: a Phase 3, multicenter, randomized, double-blind study

Masaomi Nangaku, Kazuoki Kondo, Kiichiro Ueta, Yoshimasa Kokado, Genki Kaneko, Hiroki Matsuda, Yutaka Kawaguchi, Yasuhiro Komatsu, Masaomi Nangaku, Kazuoki Kondo, Kiichiro Ueta, Yoshimasa Kokado, Genki Kaneko, Hiroki Matsuda, Yutaka Kawaguchi, Yasuhiro Komatsu

Abstract

Background: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis.

Methods: The efficacy and safety of vadadustat, compared with darbepoetin alfa, was determined in a Phase 3 double-blind study in Japanese anemic patients on hemodialysis. Patients receiving erythropoiesis-stimulating agents (ESAs) were randomized and switched to either vadadustat or darbepoetin alfa for 52 weeks. Doses were adjusted to maintain a hemoglobin (Hb) level of 10.0-12.0 g/dL. The primary endpoint was average Hb level at Weeks 20 and 24.

Results: Of the 323 randomized patients, 120 and 135 completed the 52-week treatment period in the vadadustat and darbepoetin alfa groups, respectively. The average Hb levels at Weeks 20 and 24 [least square mean (LSM) and 95% confidence interval (CI)] were 10.61 (10.45-10.76) and 10.65 (10.50-10.80) g/dL in the vadadustat and darbepoetin alfa groups, respectively, demonstrating vadadustat's noninferiority to darbepoetin alfa (difference: -0.05 g/dL; 95% CI -0.26 to 0.17). In both groups, the mean Hb levels were maintained within the target range for 52 weeks. Furthermore, irrespective of patient backgrounds, the LSMs of Hb at Week 52 were within the target range. The most common adverse events were nasopharyngitis, diarrhea and shunt stenosis, which occurred at similar frequencies in both groups. No new safety concerns were identified.

Conclusions: Vadadustat was as well-tolerated and effective as darbepoetin alfa in maintaining Hb levels within the target range. The findings suggest that vadadustat can be an alternative to ESA in the management of anemia in Japanese hemodialysis patients receiving ESA (ClinicalTrials.gov, NCT03439137).

Keywords: anemia; chronic kidney disease; hemodialysis; hypoxia-inducible factor prolyl hydroxylase inhibitor; vadadustat.

© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

Graphical abstract
Graphical abstract
FIGURE 1
FIGURE 1
Mean Hb levels and dose of study drug over time. (a) Mean Hb levels, (b) mean daily doses of vadadustat and (c) mean weekly doses of darbepoetin alfa. Data represent mean and 95% CI. BL, baseline.
FIGURE 2
FIGURE 2
Mean Hb levels and dose in vadadustat-treated subgroups stratified by baseline Hb. (a) Mean Hb levels and (b) mean daily doses of vadadustat. Data represent mean and 95% CI. BL, baseline.
FIGURE 3
FIGURE 3
Iron-related parameters. (a) Serum ferritin, (b) TSAT, (c) TIBC, (d) hepcidin, (e) MCV, (f) MCH, (g) MCHC, (h) RDW and (i) monthly dose of IV iron. Data represent mean and 95% CI. Asterisks indicate significant differences between Week 52 LOCF and baseline, except for monthly dose of IV iron, which is between Weeks 48–52 and screening (paired t-test; *P < 0.05, **P < 0.01). BL, baseline.
FIGURE 4
FIGURE 4
Subgroup analyses for LSM Hb at Week 52 and dose of study drug during Weeks 48–52. The results of a prespecified subgroup analysis with respect to the efficacy are shown. Error bars indicate 95% CI. BL, baseline.

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