Efficacy and Cardiovascular Safety of Roxadustat in Dialysis-Dependent Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies

Abstract

Introduction: This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients.Methods: Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using leastsquares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE? (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE? were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. Results: In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE? in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE? : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE? (HR 1.13,

Pleotropic effects of hypoxia-inducible factor-prolyl hydroxylase domain inhibitors: are they clinically relevant?

“…Regarding cardiovascular risk in clinical trials, roxadustat demonstrated a similar cardiovascular safety profile and overall mortality compared with ESAs in a pooled analysis of cardiovascular safety of dialysis-dependent CKD [86].…”

“…In subgroup analysis, patients who received roxadustat compared with ESA in the incident dialysis subgroup had a lower risk of all-cause mortality as well as time to the first cardiovascular event than those in the stable dialysis subgroup [86]. In another roxadustat study in nondialysis CKD patients, there was no difference in cardiovascular risk between roxadustat and placebo group [56].…”

Roxadustat: Not just for anemia

“…In addition, approximately 10% of patients are resistant to ESAs and require higher doses to achieve the recommended Hb target ( Akizawa et al, 2020c ). However, use of high-dose ESAs appears to increase the risk of adverse cardiovascular effects and mortality ( Besarab et al, 2015 ; Barratt et al, 2021 ). These findings led the US Food and Drug Administration (FDA) to recommend use of the lowest possible dose of an ESA that can achieve an adequate Hb level without the need for transfusions ( Becker and Saad, 2017 ).…”

Debate: Are Hydroxylase Inhibitors Stabilizers a Viable Alternative to Erythropoiesis-Stimulating Agents in the Management of Anemia in CKD? CON

“…Roxadustat had a robust phase 3 global clinical program consisting of 4 studies in NDD patients (3 placebo-controlled, n = 4,277 and 1 ESA controlled, n = 616) and 4 studies in ESKD patients on dialysis (all ESA controlled, n = 4,714). Using an upper CI bound of 1.30, roxadustat was non-inferior to placebo in major adverse cardiovascular outcomes (MACE) in NDD-CKD patients (HR 1.10, 95% CI: 0.96–1.27) [8] and non-inferior to epoetin in MACE in ESKD patients requiring dialysis (HR 1.09; 95% CI: 0.95–1.26) [9]. Roxadustat’s new drug application (NDA) came before the US FDA Cardiovascular and Renal Drugs Advisory Committee in July 2021, at which time the FDA briefing document [10] revealed numerous safety issues which were not apparent in peer-reviewed publications from the phase 3 clinical trials.…”

“…Due to their upregulating transcription of many genes related to iron absorption and transport as well as their indirect downregulation of hepcidin synthesis, HIF-PHIs have been shown to decrease iron requirements compared to ESA in NDD-CKD patients [16] and ESKD patients on dialysis treated with roxadustat [9, 17]; but there was no difference in iron requirements compared to ESA among NDD-CKD [18]or ESKD patients on dialysis treated with vadadustat [19]. Sub-analysis of the phase 3 global clinical trials of roxadustat versus epoetin in ESKD patients on dialysis with ferritin >500 ng/mL revealed efficacy of roxadustat in maintaining target Hb ∼11 g/dL with minimal dosage change over 52 weeks, whereas an average 19% epoetin dose increase was required to maintain Hb ∼10.5 g/dL [20].…”