#2962 EFFICACY AND SAFETY OF ROXADUSTAT IN NON-DIALYSIS-DEPENDENT CKD PATIENTS WITH OR WITHOUT INFLAMMATION: A POOLED ANALYSIS OF FOUR PHASE 3 STUDIES

Abstract

Abstract Background and Aims Chronic kidney disease (CKD)-associated anemia is commonly treated with erythropoiesis-stimulating agents (ESAs); however, some patients respond inadequately to ESAs. Inflammation may be a cause of ESA hyporesponsiveness. Roxadustat, an oral medication, is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has shown efficacy in patients with anemia of CKD. This pooled analysis examined the efficacy and safety of roxadustat in correcting hemoglobin (Hb) levels in subgroups of patients with non−dialysis-dependent (NDD) CKD with or without inflammation at baseline. Method Data from four phase 3, randomized, placebo-controlled (OLYMPUS [NCT02174627], ALPS [NCT01887600], ANDES [NCT01750190]) or erythropoiesis-stimulating agent−controlled (ESA; DOLOMITES [NCT02021318]) studies in patients with NDD CKD were pooled for this analysis. Mean Hb change from baseline to Weeks 28−52 and mean weekly total roxadustat dose (mg/kg body weight) at Week 24 in patients with or without inflammation at baseline (as determined by high-sensitivity C-reactive protein [hsCRP] levels divided into quintiles) were evaluated with an analysis of covariance model with baseline Hb and baseline estimated glomerular filtration rate as covariates. Safety data were summarized descriptively. Results In total, 3573 patients with NDD-CKD (roxadustat N = 2068; placebo = 1212; ESA N = 293) were evaluated. At baseline, the mean [SD] Hb levels (g/dL) for roxadustat (hsCRP quintiles 1−5: 9.17 [0.82], 9.26 [0.68], 9.18 [0.75], 9.15 [0.74], 9.08 [0.82]), placebo (hsCRP quintiles 1−5: 9.09 [0.74], 9.20 [0.71], 9.15 [0.69], 9.09 [0.71], 9.01 [0.76]), and ESA (hsCRP quintiles 1−5: 9.53 [0.69], 9.53 [0.64], 9.54 [0.73], 9.60 [0.66], 9.53 [0.71]) were similar across hsCRP quintiles. The mean Hb change from baseline to Weeks 28–52 was greater with roxadustat than with placebo, and comparable between roxadustat and ESA, regardless of inflammation at baseline (Fig. 1). At Week 24, roxadustat dose was not increased in patients across hsCRP quintiles (hsCRP quintiles 1−5: 3.3, 3.0, 2.7, 3.1, 3.1 mg/kg, respectively). Roxadustat dose was not significantly higher at Week 24 for patients with moderate-to-high baseline hsCRP levels (quintile 4, >3.48 to ≤8.67 mg/L; least squares mean [LSM], 3.05; 95% CI, 2.80−3.30; quintile 5, >8.67 mg/L; LSM, 3.10; 95% CI, 2.83−3.36) compared with patients with low baseline hsCRP levels (quintile 1, ≤0.71 mg/L; LSM, 3.30; 95% CI, 3.04−3.56; treatment comparison between quintile 1 and quintile 4: LSM difference, 0.25; 95% CI, −0.11 to 0.61; treatment comparison between quintile 1 and quintile 5: LSM difference, 0.20; 95% CI, −0.17 to 0.57; Fig. 2), indicating that patients with increased inflammation at baseline did not consistently require a higher roxadustat dose. The overall percentages of patients with at least one treatment-emergent adverse event were similar across hsCRP quintiles for patients treated with roxadustat (hsCRP quintiles 1−5: 88.7, 91.4, 90.3, 90.7, 90.5), placebo (hsCRP quintiles 1−5: 88.2, 84.5, 89.4, 88.5, 87.9), and ESA (hsCRP quintiles 1−5: 89.1, 90.9, 91.4, 94.1, 94.8). The most common treatment-emergent adverse events were hypertension (hsCRP quintiles 1−5 [%]; roxadustat: 16.8, 16.5, 17.4, 22.2, 18.9; placebo: 7.9, 9.5, 11.8, 9.3, 8.5; ESA: 45.7, 36.4, 39.7, 22.1, 31.2), end-stage renal disease (hsCRP quintiles 1−5 [%]; roxadustat: 21.3, 22.7, 21.1, 24.6, 23.1; placebo: 13.8, 15.9, 15.3, 18.1, 16.5; ESA: 32.6, 36.4, 34.5, 39.7, 36.4), and decreased glomerular filtration rate (hsCRP quintiles 1−5 [%]; roxadustat: 4.6, 5.0, 4.5, 5.3, 5.1; placebo: 2.0, 2.0, 2.4, 1.3, 3.1; ESA: 13.0, 22.7, 19.0, 13.2, 16.9). Conclusion Independent of baseline inflammation status, roxadustat increased Hb levels greater than placebo and comparable to ESA with a similar safety profile. Patients with high baseline hsCRP did not require increased roxadustat doses to maintain Hb levels up to Week 24. These data suggest that roxadustat is effective in patients with anemia of NDD CKD regardless of inflammation status.