Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients

Abstract

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness.

Methods: Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated.

Results: Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses.

Discussion/conclusion: The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.

Keywords: Anemia; Chronic kidney disease; Erythropoiesis-stimulating agent; Hemoglobin; Roxadustat.

Fig. 1

Allocated dose (mean, SD) of study drug per intake in the last 6 weeks (AAD/6W). Subgroup factors presented are ERI category by quartile (a), iron repletion category (b), DM status (c), eGFR (d), primary disease of CKD (e), concomitant ACEi/ARB use (f), GNRI quintile (g), and PNI quartile (h). CKD, chronic kidney disease; ERI, erythropoiesis-stimulating agent resistance index; SD, standard deviation; eGFR, estimated glomerular filtration rate; DM, diabetes mellitus; ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; GNRI, geriatric nutritional risk index; PNI, prognostic nutritional index; AAD/6W, average allocated dose of roxadustat or darbepoetin alfa per administration in the last 6 weeks.

Fig. 2

Ratio between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W. Subgroup factors presented are ERI category by quartile (a), hs-CRP (b), DM status (c), eGFR (d), primary disease of CKD − CGN (e), DN, NS, and other, concomitant ACEi/ARB use (f), GNRI quintile (g), and PNI quartile (h). CKD, chronic kidney disease; ERI, erythropoiesis-stimulating agent resistance index; DA, darbepoetin alfa; eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein; DM, diabetes mellitus; CGN, chronic glomerular nephritis; DN, diabetic nephropathy; NS, nephrosclerosis; ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; GNRI, geriatric nutritional risk index; PNI, prognostic nutritional index; AAD/6W, average allocated dose of roxadustat or darbepoetin alfa per administration in the last 6 weeks.