POS-284 CARDIOVASCULAR OUTCOMES AND EXPLORATORY ANALYSES BY ACHIEVED HB LEVELS IN POOLED PHASE 3 TRIALS OF ROXADUSTAT IN DIALYSIS-DEPENDENT PATIENTS WITH ANEMIA OF CHRONIC KIDNEY DISEASE

Abstract

Lower hemoglobin (Hb) in patients on dialysis is associated with increased risk of hospitalization and mortality (Lacson et al. Am J Kidney Dis. 2009). 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. NEJM 1998; Singh et al. NEJM 2006; Drüeke et al. NEJM. 2006; Pfeffer et al. NEJM 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 patients with anemia of dialysis-dependent (DD) chronic kidney disease (CKD) treated with roxadustat. Pooled data from three pivotal, phase 3, randomized, open-label, epoetin alfa–controlled studies of roxadustat for the treatment of anemia in patients with DD-CKD were assessed. Patients requiring dialysis and anemia treatment were 1:1 randomized to receive roxadustat or epoetin alfa. Primary efficacy endpoint for the US FDA submission was the mean change from baseline in Hb averaged over Weeks 28-52, 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 for the treatment period and within 7 days of the last dose of study medication (OT+7). Exploratory analyses included incidence rates of MACE and MACE+ among patients randomized to roxadustat, evaluated based on 1) Hb level immediately before the event, defined as the most recent central laboratory Hb value that preceded the onset of the event, and 2) maximum Hb level in the first 12 treatment weeks. For this analysis, events occurring within 12 weeks following randomization were excluded. The ITT population included 3890 patients (1943 roxadustat and 1947 epoetin alfa). Mean baseline Hb was 9.6-9.7 g/dL. Mean (SD) changes in Hb from baseline averaged over Weeks 28–52, regardless of rescue therapy, were 1.22 (1.49) and 0.99 (1.51) g/dL in the roxadustat and epoetin alfa groups, respectively (least squares mean treatment difference: 0.26 [95% CI: 0.20, 0.33; P<0.0001]). Comparing roxadustat with epoetin alfa, HR for MACE was 0.96 (95% CI 0.82, 1.13) & MACE+ HR was 0.86 (0.74, 0.98; P=0.028) in the pooled population. In roxadustat-treated patients, the MACE and MACE+ rates were highest when Hb was <8 g/dL, 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 DD-CKD population, roxadustat generally maintained Hb to 11±1 g/dL during weeks 28-52. Risk of MACE in roxadustat-treated patients was not increased compared to epoetin alfa. Furthermore, roxadustat lowered the risk of MACE+ compared to epoetin alfa. In roxadustat-treated patients, MACE and MACE+ incidence rates were lowest when achieved Hb levels were ≥10 g/dL.