A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis

Abstract

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia in Japan for patients with dialysis-dependent (DD) chronic kidney disease (CKD).

Objective: Multicenter, randomized, open-label, noncomparative, phase 3 study to evaluate roxadustat for anemia of non-dialysis-dependent (NDD) CKD in Japan.

Methods: Erythropoiesis stimulating agent (ESA)-naïve NDD-CKD patients were randomized to roxadustat (initial dose, 50 or 70 mg 3 times weekly), titrated to maintain hemoglobin (Hb) within 10.0-12.0 g/dL, for ≤24 weeks. Patients with either transferrin saturation of ≥5% or serum ferritin of ≥30 ng/mL during the screening period were eligible. Endpoints included response rate (proportion of patients achieving Hb ≥10.0 or ≥10.5 g/dL and Hb increase ≥1.0 g/dL from baseline) at end of treatment; average Hb (weeks 18-24); change of average Hb from baseline to weeks 18-24; maintenance rate (proportion of patients achieving Hb 10.0-12.0 g/dL at weeks 18-24); rate of rise (RoR) of Hb from weeks 0-4, discontinuation, or dose adjustment. Adverse events were monitored throughout the study.

Results: Of 135 patients who provided informed consent, 100 were randomized and 99 received roxadustat (50 mg, n = 49; 70 mg, n = 50). The mean (SD) dose of roxadustat per intake at week 22 was 36.3 (22.7) mg in the roxadustat 50 mg group and 36.8 (16.0) mg in the roxadustat 70 mg group. Prior medications included oral iron therapy (20.2%) and intravenous iron therapy (1.0%). Overall response rate (95% CI) was 97.0% (91.4, 99.4; Hb ≥10.0 g/dL) and 94.9% (88.6, 98.3; Hb ≥10.5 g/dL). Mean (SD) Hb (weeks 18-24) was 11.17 (0.62) g/dL. Mean (SD) change of Hb from baseline (weeks 18-24) was 1.34 (0.86) g/dL. Maintenance rate (95% CI) was 88.8% (80.3, 94.5) among patients with ≥1 Hb measurement during weeks 18-24. Mean (SD) RoR of Hb was 0.291 (0.197) g/dL/week (50 mg) and 0.373 (0.235) g/dL/week (70 mg). Nasopharyngitis and hypertension were the most common adverse events.

Conclusion: Roxadustat increased and maintained Hb in ESA-naïve, partially iron-depleted NDD-CKD patients with anemia.

Keywords: Anemia; Chronic kidney disease; Erythropoiesis-stimulating agent naïve patients; Non-dialysis-dependent patients; Roxadustat.

Fig. 1

Disposition of patients. Reasons for discontinuation before randomization: n = 17, did not meet Hb criteria; n = 6, considered ineligible by the investigator; n = 5, withdrawal by patient; n = 3, positive for hepatitis B virus surface antigen or hepatitis C virus antibody at prescreening or positive for human immunodeficiency virus in a past test; n = 1, concurrent retinal neovascular lesion or macular edema requiring treatment; n = 1, treated with ESA, protein anabolic hormone, testosterone enanthate, or mepitiostane within 6 weeks before prescreening; n = 1, history of hospitalization for treatment of stroke, myocardial infarction, or pulmonary embolism within 12 weeks before prescreening; n = 1, lost to follow-up. FAS, full analysis set; SAF, safety analysis set; TEAE, treatment-emergent adverse event.

Fig. 2

Mean (SD) allocated dose of roxadustat per intake (safety analysis set).

Fig. 3

Mean (SD) hemoglobin levels (full analysis set). EoT, end of treatment; PSC, prescreening; SC, screening.