Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, open-label, active-controlled study (DOLOMITES)

Abstract

Background Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD). Methods This randomised, open-label, active-controlled phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non–dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin within 10.0–12.0 g/dL. The primary endpoint was haemoglobin response in the full analysis set (FAS), defined as haemoglobin ≥11.0 g/dL and haemoglobin change from baseline (CFB) ≥1.0 g/dL in patients with baseline haemoglobin >8.0 g/dL or CFB ≥2.0 g/dL in patients with baseline haemoglobin ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (noninferiority margin, -15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous iron use, change in mean arterial pressure (MAP), and time to hypertension occurrence. Adverse events were assessed. Results Of 616 randomised patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Haemoglobin response with roxadustat was noninferior to DA (roxadustat: 256/286, 89.5% vs. DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval, 5.66-17.36%). Roxadustat maintained haemoglobin for up to 2 years. Roxadustat was noninferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first intravenous iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACE) and MACE + (MACE: 0.81 [0.52, 1.25], P = 0.339; MACE+: 0.90 [0.61, 1.32], P = 0.583). Conclusion Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining haemoglobin levels for up to 104 weeks.

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

“…The transient inhibition of HIF prolyl hydroxylases by HIF-PHIs mimics the body's natural response to hypoxia in the presence of normal oxygen levels [14]. Roxadustat has been compared to placebo and ESAs with favorable efficacy and safety findings in phase 3 studies, resulting in its approval in Chile, China, the European Union (EU), Japan, and South Korea for non-dialysisdependent (NDD) and DD CKD [15][16][17][18][19][20][21][22][23][24][25][26]. The roxadustat development program included four studies in the DD population of which three were similarly designed (SIERRAS, HIMALAYAS, and ROCKIES) [24][25][26] and the fourth (PYR-ENEES) differed in comparator [23].…”

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

“…In animal models, molidustat also showed blood pressure lowering effect in an adenine-induced CKD model (Li L. et al, 2020). However, clinical trials did not show an advantage of HIF-PHIs over regulating blood pressure in CKD patients either with or without dialysis (Barratt et al, 2021;Chen et al, 2021). Daprodustat even showed a hypertensive effect at high doses (attributed to a rapid rate of rise of Hb) (Meadowcroft et al, 2019).…”

Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: “Can the Promise Be Kept?”

“…Finally, in June 2021 the results of the DOLOMITES study [66] were disclosed. This is a randomized, open-label, phase 3 study that compares the anemia control efficacy and safety of Roxadustat versus darbepoetin in 616 NDD-CKD patients.…”