Efficacy and Cardiovascular Safety of Roxadustat for Treatment of Anemia in Patients with Non–Dialysis-Dependent CKD

Abstract

Background and objectivesWe evaluated the efficacy and cardiovascular safety of roxadustat versus placebo by analyzing data pooled from three phase 3 studies of roxadustat in patients with non–dialysis-dependent CKD and CKD-related anemia.Design, setting, participants, & measurementsIn the three phase 3, double-blind studies of roxadustat versus placebo evaluating the treatment of CKD-related anemia in patients not requiring dialysis, the primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28–52, regardless of rescue therapy. The primary cardiovascular safety end point was a composite measure of major adverse cardiovascular events (MACE; all-cause mortality, myocardial infarction, stroke). MACE plus (MACE+; MACE plus unstable angina and heart failure requiring hospitalization) and all-cause mortality were key secondary safety end points. These safety end points were adjudicated.ResultsA total of 4277 patients with non–dialysis-dependent CKD were randomized (roxadustat, n=2391; placebo, n=1886). Baseline characteristics were comparable between groups; the mean (SD) hemoglobin was 9.1 (0.7) g/dl and mean eGFR was 20 (12) ml/min per 1.73 m2. Patients treated with roxadustat versus those treated with placebo showed a mean change from baseline in hemoglobin averaged over weeks 28–52, regardless of rescue therapy, of 1.9 versus 0.2 g/dl, a treatment difference of 1.7 (95% confidence interval [95% CI], 1.7 to 1.8). Roxadustat reduced the need for red blood cell transfusion in the first 52 weeks versus placebo (6.1 versus 20.4 per 100 patient-exposure years, respectively; hazard ratio [HR], 0.26; 95% CI, 0.21 to 0.32). There were no increased risks of MACE (HR, 1.10; 95% CI, 0.96 to 1.27), MACE+ (HR, 1.07; 95% CI, 0.94 to 1.21), all-cause mortality (HR, 1.08; 95% CI, 0.93 to 1.26), or individual MACE+ components in patients treated with roxadustat versus those treated with placebo.ConclusionsRoxadustat was more effective than placebo at increasing hemoglobin in patients with non–dialysis-dependent CKD and anemia, while decreasing transfusion rate and being noninferior to placebo with respect to risk of MACE.Clinical Trial registry name and registration number:A Study of FG-4592 for the Treatment of Anemia in Chronic Kidney Disease Patients Not Receiving Dialysis, NCT01750190; Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (ALPS), NCT01887600; Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis, NCT02174627

Roxadustat for the treatment of anemia in patients with lower‐risk myelodysplastic syndrome: Open‐label, dose‐selection, lead‐in stage of a phase 3 study

“…Previous studies in patients with CKD demonstrated that roxadustat was effective at increasing and maintaining hemoglobin levels and was generally well tolerated 20,27–30,32,33,41 . Adverse reactions reported in the pooled studies in the CKD patients included vascular access thrombosis, deep vein thrombosis, and seizures.…”

“…Previous studies in patients with CKD demonstrated that roxadustat was effective at increasing and maintaining hemoglobin levels and was generally well tolerated. 20,[27][28][29][30]32,33,41 Working Group 2006 and 2018 hematological response criteria in patients with MDS included in clinical trials could be applied in this clinical study. 42,43 Clinically meaningful features, such as a screening period of 16 weeks before the anticipated treatment start, refinement of the RBC transfusion burden by dividing patients into three categories (nontransfused, low transfusion burden, and high transfusion burden), and definition of the response duration of at least 16 weeks, will be taken into consideration in future larger studies.…”

“…Roxadustat has recently been approved in China, 20,21 Japan, 24–26 Chile, South Korea, UK, and Europe for the treatment of anemia of chronic kidney disease (CKD). Roxadustat has been investigated for safety and efficacy in multiple global and US‐based clinical development programs 27–33 . In addition to anemia of CKD (in dialysis‐ and non‐dialysis‐dependent patients) and MDS, roxadustat has shown efficacy in improving anemia in a Phase 2 study for the treatment of patients with chemotherapy‐induced anemia (data on file).…”

“…Roxadustat has been investigated for safety and efficacy in multiple global and US-based clinical development programs. [27][28][29][30][31][32][33] In addition to anemia of CKD (in dialysis-and non-dialysis-dependent patients) and MDS, roxadustat has shown efficacy in improving anemia in a Phase 2 study for the treatment of patients with chemotherapy-induced anemia (data on file).…”

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.…”