Roxadustat for the Maintenance Treatment of Anemia in Patients with End-Stage Kidney Disease on Stable Dialysis: A European Phase 3, Randomized, Open-Label, Active-Controlled Study (PYRENEES)

Abstract

Introduction: Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD). This European, phase 3, randomized, open-label, active-controlled study investigated efficacy and safety of roxadustat in patients with end-stage kidney disease on dialysis for at least 4 months.

Methods: Patients were randomized to switch from an erythropoiesis-stimulating agent (ESA) (epoetin alfa or darbepoetin alfa) to roxadustat three times/week or to continue their previous ESA. Roxadustat and ESA doses were adjusted to maintain hemoglobin within 10.0-12.0 g/dL during the treatment period (day 1 up to 52-104 weeks). Primary endpoints were hemoglobin change from baseline (CFB) to the average of weeks 28-36 without rescue therapy and hemoglobin CFB to the average of weeks 28-52 regardless of rescue therapy. Treatment-emergent adverse events (TEAEs) were assessed descriptively.

Results: Of 1081 screened patients, 836 were randomized and received treatment (roxadustat, n = 415; ESA, n = 421). The least squares means (95% CI) of the treatment difference (roxadustat - ESA) for hemoglobin CFB to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively, demonstrating non-inferiority of roxadustat to ESA (non-inferiority margin of - 0.75 g/dL). The proportions of patients who achieved target hemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Roxadustat was superior to ESA in decreasing LDL cholesterol from baseline to the average of weeks 12-28. Serious TEAEs occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhea.

Conclusion: Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels in this cohort of patients with anemia of CKD on dialysis for at least 4 months who were previously treated with ESAs. Observed TEAEs were consistent with previous studies.

Keywords: Chronic kidney disease; Hemodialysis; Peritoneal dialysis.

Fig. 1

Study flow chart. ^aHemoglobin was maintained within 10–12 g/dL. ^bThe choice of anemia treatment was at the discretion of the investigator. ^cPatients could have taken epoetin (i.e., epoetin alfa, beta, theta, zeta, delta, or omega) or darbepoetin alfa prior to randomization. ^dPatients received epoetin alfa if they were on epoetin (i.e., epoetin alfa, beta, theta, zeta, delta, or omega) prior to randomization or darbepoetin alfa if they were on darbepoetin alfa prior to randomization. ESA erythropoiesis-stimulating agent, R randomization

Fig. 2

Patient disposition. ESA erythropoiesis-stimulating agent, GCP good clinical practices

Fig. 3

Mean (SD) hemoglobin concentrations (per protocol set). BL baseline, ESA erythropoiesis-stimulating agent, SD standard deviation

Fig. 4

Mean (SD) low-density lipoprotein cholesterol by visit (full analysis set). ESA erythropoiesis-stimulating agent, LDL low-density lipoprotein