A Placebo-Controlled, Randomized Trial of Enarodustat in Patients with Chronic Kidney Disease Followed by Long-Term Trial

Abstract

Background: Enarodustat (JTZ-951) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that mimics adaptive responses to hypoxic conditions and may provide a new therapeutic approach for managing anemia in patients with chronic kidney disease (CKD). We evaluated the efficacy, safety, and maintenance dose of enarodustat in anemic patients with CKD not on dialysis.

Methods: Erythropoiesis-stimulating agent (ESA) naïve patients (correction group) and patients on a stable dose of ESA (conversion group) were randomized to receive 2, 4, or 6 mg of enarodustat or placebo once daily for 6 weeks in a double-blind manner (Period 1) followed by 24 weeks of open enarodustat treatment to maintain their hemoglobin (Hb) levels within a target range of 10.0-12.0 g/dL in reference to a dose adjustment algorithm (Period 2).

Results: In the correction group, Hb level increase rate per week increased in a dose-response manner. The proportion of subjects in the conversion group who maintained Hb levels within ± 1.0 g/dL of baseline did not differ between each enarodustat arm and placebo arm during Period 1. Over 70% of subjects in both groups maintained Hb levels within the target range at the end of treatment in Period 2. The mean prescribed doses were 3.58 and 3.74 mg/day in the correction group and the conversion group, respectively. Enarodustat was associated with decreases in hepcidin and ferritin and increased total iron-binding capacity and was generally well tolerated.

Conclusions: Enarodustat corrects and maintains Hb levels in anemic patients with CKD not on dialysis.

Keywords: Anemia in chronic kidney disease; Enarodustat; Hepcidin; Hypoxia-inducible factor prolyl hydroxylase inhibitor; Randomized trial.

Fig. 1

Changes in hemoglobin levels over time. (a) Correction group; (b) conversion group. Each point indicates mean hemoglobin level in each treatment arm on each observation day; bars indicate SD. Ext, extention; F-up, follow-up.

Fig. 2

Changes in iron-related parameters (Period 1). (a) Correction group, Period 1; (b) conversion group, Period 1. Each point indicates the median value on each observation day in each treatment arm; bars indicate quartile deviations. Post hoc analysis was performed only for changes in Week 6, which were compared between the placebo arm and each enarodustat arm using the Wilcoxon rank sum test (significance level: 5%, 2-sided). Adjustment for multiplicity was not performed. * p < 0.05, ** p < 0.0001. BL, baseline; TIBC, total iron-binding capacity; TSAT, transferrin saturation.