A Phase 3 Study of Enarodustat in Anemic Patients with CKD not Requiring Dialysis: The SYMPHONY ND Study

Abstract

Introduction: Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that might be a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy (noninferiority to darbepoetin alfa [DA]) and safety of enarodustat in Japanese anemic patients with CKD not requiring dialysis.

Methods: Erythropoiesis-stimulating agent (ESA)-naïve patients and ESA-treated patients were randomized at a 1:1 ratio to receive enarodustat orally once daily or DA subcutaneously every 2 or 4 weeks for 24 weeks, respectively. Subjects in each arm had dose adjustments every 4 weeks to maintain their hemoglobin (Hb) level within the target range (10 to 12 g/dl). The primary endpoint was the difference in the mean Hb level between arms during the evaluation period defined as weeks 20 to 24 (noninferiority margin: -0.75 g/dl).

Results: The mean Hb level during the evaluation period in the enarodustat arm was 10.96 g/dl (95% confidence interval [CI]: 10.84 to 11.07 g/dl) with a difference of 0.09 g/dl (95% CI: -0.07 to 0.26 g/dl) between arms, establishing its noninferiority to DA. Nearly 90% of subjects in both arms maintained a mean Hb level within the target range. Compared with DA, enarodustat was associated with decreased hepcidin and ferritin, and increased total iron-binding capacity. There were no apparent differences in the incidence of adverse events between arms (65.4% [enarodustat], 82.6% [DA]).

Conclusions: The efficacy of enarodustat was comparable to DA in anemic patients with CKD not requiring dialysis. No new safety concerns were identified compared with DA.

Keywords: anemia in chronic kidney disease; comparative study; enarodustat; hepcidin; hypoxia-inducible factor prolyl hydroxylase inhibitor.

Graphical abstract

Figure 1

Time course of Hb levels over time (full analysis set). (a) All subjects. (b) ESA-naïve subjects. (c) ESA-treated subjects. Each point indicates the mean Hb level in each treatment arm and bars indicate the 95% confidence interval. Hb, hemoglobin; ESA, erythropoiesis-stimulating agent; DA, darbepoetin alfa; EOT, end of treatment.

Figure 2

Changes in iron-related parameters (full analysis set). (a) ESA-naïve subjects; (b) ESA-treated subjects. Each point indicates the median value in each treatment arm and bars indicate Q1 and Q3. Post hoc analysis was performed for changes in week 24, which were compared with week 0 using the Wilcoxon signed-rank test and between both arms using the Wilcoxon rank sum test (significance level: 5%, two-sided). Adjustment for multiplicity was not performed. ∗P < 0.05 and ∗∗P < 0.0001 for comparisons with week 0, †P < 0.05 and ††P < 0.0001 for comparisons between both arms. BL, baseline; DA, darbepoetin alfa; ESA, erythropoiesis-stimulating agent; TIBC, total iron-binding capacity; TSAT, transferrin saturation.

Figure 2

Changes in iron-related parameters (full analysis set). (a) ESA-naïve subjects; (b) ESA-treated subjects. Each point indicates the median value in each treatment arm and bars indicate Q1 and Q3. Post hoc analysis was performed for changes in week 24, which were compared with week 0 using the Wilcoxon signed-rank test and between both arms using the Wilcoxon rank sum test (significance level: 5%, two-sided). Adjustment for multiplicity was not performed. ∗P < 0.05 and ∗∗P < 0.0001 for comparisons with week 0, †P < 0.05 and ††P < 0.0001 for comparisons between both arms. BL, baseline; DA, darbepoetin alfa; ESA, erythropoiesis-stimulating agent; TIBC, total iron-binding capacity; TSAT, transferrin saturation.