The Efficacy and Safety of Enarodustat for the Treatment of Anemia in Hemodialysis-Dependent Chronic Kidney Disease Patients: A Phase 3, Multicenter, Randomized, Active-Comparator (Recombinant Human Erythropoietin), Open-Label Study - The ENARODIAL Study.

Enarodustat is an oral HIF-PHI for the treatment of chronic kidney disease anemia. This phase 3, multicenter, randomized 24-week study assessed enarodustat's noninferiority to rHuEPO for treating hemodialysis-dependent CKD (HD-CKD) anemia. Overall, 100 ESAs-treated patients were randomized 1:1 to enarodustat or rHuEPO for a 24-week treatment with dose adjustment every 4 weeks to maintain hemoglobin (Hb) within target range 100-120 g/L. The primary efficacy endpoint was the between-group difference in mean Hb over weeks 20-24 (evaluation period [noninferiority margin: -10 g/L]). Safety was assessed by treatment-emergent adverse events (TEAEs). Of the 100 patients treated (enarodustat: 50; rHuEPO: 50), 93 completed the study. Demographic and baseline characteristics were comparable. During the evaluation period, the mean Hb level was 106.81 g/L in the enarodustat group and 99.68 g/L in the rHuEPO group. Enarodustat was noninferior to rHuEPO (least squares mean difference: 7.47 g/L [95% confidence interval: 4.17, 10.78]; p < 0.001). The mean Hb level in the enarodustat group remained within the target range throughout the treatment period, with a maintenance rate of 79.6% during weeks 20-24 versus 51.0% for rHuEPO. After switching from ESAs, the enarodustat group showed increased total iron-binding capacity, transferrin, and serum iron, decreased hepcidin by week 4, and increased RET% by week 2. TEAEs incidences were comparable (enarodustat: 90.0%, rHuEPO: 90.0%), with no additional safety concerns for enarodustat. Enarodustat was noninferior to rHuEPO for the treatment of anemia in HD-CKD patients, with good safety and tolerability over 24 weeks.