Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS)

Abstract

Background Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) for the treatment of chronic kidney disease (CKD) anemia. Methods This phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with stage 3-5 CKD not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52-104 weeks. This study examined two primary efficacy endpoints: European Union (EMA) - hemoglobin (Hb) response, defined as Hb ≥ 11.0 g/dL that increased from baseline by ≥ 1.0 g/dL in patients with Hb > 8.0 g/dL or ≥ 2.0 g/dL in patients with baseline Hb ≤ 8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; United States (FDA) - change in Hb from baseline to the average Hb level during Weeks 28-52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined. Results A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response (odds ratio: 34.74 [95% CI: 20.48, 58.93]) and change in Hb from baseline (roxadustat - placebo: +1.692 [95% CI: 1.52, 1.86]; both P<0.001). Superiority of roxadustat was demonstrated for LDL cholesterol change from baseline, and time to first use of rescue medication (both P<0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%). Conclusions Roxadustat demonstrated superior efficacy versus placebo both in terms of Hb response rate and change in Hb from baseline. The safety profiles of roxadustat and placebo were comparable.

Novel Iron Parameters in Patients with Type 2 Diabetes Mellitus in Relation to Kidney Function

“…HIF also controls the expression of the proteins playing a role in iron metabolism and utilization (the upregulation of transferrin, soluble transferrin receptor 1 (sTfr1), ceruloplasmin, divalent metal transporter 1 (DMT1), duodenal cytochrome b (Dcytb); and the downregulation of hepcidin). Increases in soluble transferrin receptor 1 improve iron availability, given its role as a carrier protein for transferrin required to import iron into the cell [64]. Researchers suggest that hepcidin suppression most likely results from the stimulation of erythropoiesis, as it seems that hepcidin is not a direct transcriptional target of HIF.…”

Safe and Effective Treatment for Anemic Patients With Chronic Kidney Disease: An Updated Systematic Review and Meta-Analysis on Roxadustat

“…When the mean and LSM values were separated, the pooled results also showed that roxadustat significantly raised the Hb level both in the DD-CKD patients (online Supplementary Figure S1A) and in the NDD-CKD patients (online Supplementary Figure S1B). Shutov et al, (2021) (five trials for DD-CKD patients, eight trials for NDD-CKD patients) with 7,488 participants enrolled. Subgroup analysis revealed that there was no significant difference about Hb response between roxadustat and ESAs in the DD-CKD patient group (OR: 1.27; 95% CI: 0.86-1.87; p 0.22; Figure 3B and Table 3).…”

“…In addition, the duration of the studies enrolled in previous meta-analyses was relatively short, with a maximum follow-up of 26 weeks. Recently, the results of five large phase 3 clinical trials Akizawa et al (2020a), Coyne et al (2021), Fishbane et al (2021), Provenzano et al (2021), Shutov et al (2021) of roxadustat were released, so we updated the meta-analysis. Randomized controlled trials that assessed the efficacy (hemoglobin levels and response) and safety (treatment-emergent adverse events) of roxadustat in DD-CKD and NDD-CKD anemia patients comparing with ESAs or placebo were retriedved with an aim to generate a robust conclusion on the effect of and safety of roxadustat.…”

Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents

“…Collectively, data from clinical trials of HIF-PH inhibitors, namely roxadustat [115][116][117][118][119][120][121][122][123][124][125][126][127], daprodustat [128][129][130][131][132][133][134][135], desidustat [136], enarodustat [137,138], molidustat [139][140][141][142][143], and vadadustat [144][145][146][147][148][149], have clearly shown these agents are efficacious in increasing Hb and decreasing hepcidin levels in patients with anemia of CKD (Table 2). Indeed, a recent meta-analysis of 22 trials found that HIF-PH inhibitors provided a 0.96 and 1.78 g/dL greater weighted mean increases of Hb levels from baseline compared with control (placebo or ESA) in patients with DD-CKD or NDD-CKD, respectively [150].…”

“…In a single study of 836 patients on maintenance dialysis in central Europe, all-cause mortality was 15.4% with roxadustat and 12.1% with epoetin alfa or darbepoetin alfa [159]. Recently reported phase 3 studies in patients with NDD-CKD stages 3-5 found no significant difference in the risk of mortality [124] or in the incident mortality rate [127] in patients treated with roxadustat compared with placebo. In a phase 3 study of patients on dialysis >2 weeks and ≤4 months, the number of fatal treatment-emergent adverse events was similar between the roxadustat and epoetin alfa groups [126].…”