Pooled Efficacy and Cardiovascular Analysis of Roxadustat Compared with Placebo in Anemia Correction in Chronic Kidney Disease Patients Not on Dialysis

Introduction

Anemia affects >50% of patients with chronic kidney disease (CKD), stages 1-5 (Stauffer ME, Fan T. PLoS One 2014; 9(1): e84943.). The current standard of care for anemia of CKD is erythropoiesis-stimulating agents (ESAs) with or without IV iron supplementation and red blood cell (RBC) transfusion. In 2011, the FDA issued a warning that ESAs are associated with high risk of death and cardiovascular (CV) events (all-cause mortality, myocardial infarction, and stroke), especially at high doses. Hyporesponsiveness to ESAs is common due to CKD-related inflammation, requiring higher compensatory doses. Due to the increased risk of death and CV events, some patients with anemia of CKD are not receiving optimal doses of ESAs and RBC transfusions have increased.

Roxadustat is an oral hypoxia–inducible factor prolyl hydroxylase inhibitor that regulates erythropoiesis and iron metabolism. This integrated Phase 3 analysis examines efficacy and safety of roxadustat in CKD patients not on dialysis.

Methods

Three double-blind Phase 3 studies (FGCL-4592-060, 1517-CL-0608, and D5740C00001) of similar design compared roxadustat with placebo; data were pooled. Patients with Stage 3-5 CKD and hemoglobin (Hb) < 10.0 g/dL were randomly assigned to roxadustat or placebo. Cardiovascular endpoints were death, MI, and stroke events (MACE), and heart failure or unstable angina requiring hospitalization events (MACE+), and were adjudicated. In 1517-CL-0608, patients were followed for 2 years; FGCL-4592-060 and D5740C00001 were event-driven trials. Efficacy analyses assessed Hb change from baseline (CFB); rescue therapy (transfusion, IV iron, and ESAs); estimated glomerular filtration rate (eGFR); and low-density lipoprotein cholesterol (LDL).

Results

Overall, 4,270 patients were randomized to treatment (2,386 roxadustat, 1,884 placebo). Baseline (BL) Hb was 9.1 g/dl. The primary endpoint (mean Hb CFB over weeks 28-52) was met for each individual study (both noninferior and superior, all p-values were at least < 0.001) and was +1.85 (± 0.94) g/dL in the pooled roxadustat vs +0.13 (± 1.01) g/dL placebo groups (p < 0.0001). In the first 52 weeks, roxadustat subjects had a lower risk of rescue therapy, hazard ratio (HR) (95% CI) = 0.19 (0.16, 0.23; 81% reduction, p < 0.0001), with RBC transfusion HR (95% CI) = 0.26 (0.21, 0.32; 74% reduction, p < 0.001). Attenuation of eGFR progression among patients with BL eGFR ≥ 5 (N=2456; Δ roxadustat v. placebo in eGFR to 52 wks) was 1.6 mL/min, p < 0.0001; reduced eGFR decline by 36% (-2.8 vs. -4.4). Early LDL reduction continued through week 28, p < 0.0001. In the intent to treat population, HR for MACE events was 1.08 (95% CI 0.94, 1.24) for roxadustat compared with placebo, and 1.04 (95% CI 0.91, 1.18) for MACE+. In the subgroup with BL eGFR > 10 (n=3431), MACE HR (95% CI) = 0.99 (0.84, 1.16) and MACE+ = 0.98 (0.85, 1.14) for roxadustat v. placebo. Roxadustat patients had significantly longer MACE- and MACE+-free survival on treatment than placebo (p < 0.0001).

Conclusions

This pooled analysis of Phase 3 studies provides evidence for roxadustat superiority in anemia correction, transfusion reduction, and other clinical benefits with acceptable cardiovascular safety profile compared with placebo.