Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan

Significance Statement Although generally effective at raising hemoglobin levels to treat dialysis-dependent CKD anemia, erythropoiesis-stimulating agents such as darbepoetin alfa have safety issues and are less effective in patients with inflammation. In this randomized controlled trial in stable Japanese patients on hemodialysis previously treated with erythropoiesis-stimulating agents, the authors compared roxadustat—an oral hypoxia-inducible factor prolyl hydroxylase inhibitor previously shown to be effective in treating CKD anemia—with darbepoetin alfa. The study found that roxadustat was effective in maintaining hemoglobin within target levels and that its efficacy was noninferior to darbepoetin alfa. Consistent with previous findings, roxadustat showed an acceptable safety profile. These data confirm that oral roxadustat is a valid alternative to injectable erythropoiesis-stimulating agents for dialysis-dependent CKD anemia. Background Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia. Methods This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat’s noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10–12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18–24 ( ∆ Hb 18–24 ). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10–12 g/dl (maintenance rate) at weeks 18–24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings. Results We randomly assigned 303 patients to roxadustat ( n =151) or darbepoetin alfa ( n =152). The difference between roxadustat and darbepoetin alfa in ∆ Hb 18–24 was −0.02 g/dl (95% confidence interval, –0.18 to 0.15), confirming roxadustat’s noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18–24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18–24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups. Conclusions Roxadustat maintained hemoglobin within 10–12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports. Clinical Trial registry name and registration number A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov)