POS-258 CARDIOVASCULAR OUTCOMES AND EXPLORATORY ANALYSES BY ACHIEVED HB LEVELS IN THE POOLED PHASE 3 ROXADUSTAT STUDIES OF NON-DIALYSIS-DEPENDENT PATIENTS WITH ANEMIA OF CHRONIC KIDNEY DISEASE

Abstract

Increasing severity of anemia among patients with non-dialysis dependent (NDD) chronic kidney disease (CKD) is associated with decreased survival (Levin et al. Nephrol Dial Trans. 2006). Previous studies (NHCT, CHOIR, CREATE and TREAT) showed that ESA treatment to high Hb targets could increase mortality and cardiovascular (CV) events (Besarab et al. N Engl J Med. 1998; Singh et al. N Engl J Med. 2006; Drüeke et al. N Engl J Med. 2006; Pfeffer et al. N Engl J Med. 2009). In secondary analyses, this increased risk was associated with higher ESA doses rather than achieved Hb levels (Szczech et al. Kidney Int 2008). Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates a coordinated erythropoietic response by increasing endogenous EPO production, decreasing hepcidin, and increasing iron availability. We examined the associations between achieved Hb levels and CV outcomes in NDD patients with anemia of CKD treated with roxadustat. Pooled data from three pivotal, phase 3, randomized, double-blind, placebo-controlled studies of roxadustat for the treatment of anemia in patients with NDD-CKD were assessed. Primary efficacy endpoint for the US FDA submission was the mean change from baseline in Hb averaged over Weeks 28 to 52, regardless of rescue therapy, in all three pivotal studies. Key CV safety endpoints included time to first major adverse CV event (MACE, consisting of death, MI, and stroke) and time to first MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization); these adjudicated CV events were evaluated based on ITT analysis. Exploratory analyses included incidence rates of adjudicated MACE and MACE+ among patients randomized to roxadustat, evaluated based on 1) Hb level immediately before the event and 2) maximum Hb level in the first 12 treatment weeks (during the period of anemia correction). For this analysis, events occurring within 12 weeks following randomization were excluded. Hb level immediately before the event was defined as the most recent Hb value occurring prior to the event. The ITT population included 4277 patients with NDD-CKD (2391 roxadustat, 1886 placebo). Mean baseline Hb was 9.10 g/dL in both treatment groups. Mean (SD) changes in Hb from baseline averaged over Weeks 28–52, regardless of rescue therapy, were +1.85 (0.94) and +0.13 (1.01) g/dL in the pooled roxadustat and placebo groups (least squares mean [LSM] treatment difference: 1.72 [95% CI: 1.65, 1.79; P<0.001]); results for the individual studies were similar to the pooled data. The HR for time to MACE was 1.08 (95% CI 0.94, 1.24) for roxadustat vs. placebo and 1.04 (95% CI 0.91, 1.18) for MACE+. In the roxadustat-treated patients, the MACE and MACE+ rates were highest when Hb was <8 g/dL and decreasing as Hb increased to ≥10 g/dL, which includes categories of Hb levels 10–<11, 11–<12, and ≥12 g/dL (Table). In the NDD-CKD population, roxadustat corrected anemia and generally maintained Hb to 11±1 g/dL during weeks 28-52. Risk of MACE and MACE+ in patients treated with roxadustat were comparable to placebo in NDD patients. MACE and MACE+ incidence rates were lowest when achieved Hb levels were ≥10 g/dL.