Roxadustat Treatment of Chronic Kidney Disease-Associated Anemia in Japanese Patients Not on Dialysis: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Introduction: This study evaluated efficacy and safety/tolerability of roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, in Japanese anemic non-dialysis-dependent chronic kidney disease (NDD-CKD) patients.

Methods: In this phase 2, double-blind, 24-week study, NDD-CKD patients were randomized to oral placebo or roxadustat (50, 70, or 100 mg) three times weekly (TIW) for 6 weeks followed by dose adjustments to maintain hemoglobin (Hb) at 10-12 g/dL for 18 weeks; patients meeting pre-defined criteria were re-randomized to TIW or once-weekly dosing. The primary end point was rate of rise of Hb (g/dL/week) during the first 6 weeks; secondary end points included response rate (Hb ≥ 10.0 g/dL and increase in Hb from baseline ≥ 1 g/dL) and mean Hb and change from baseline in Hb at weeks 18-24. The main safety outcomes were vital signs, laboratory test results, electrocardiograms, and frequency of treatment-emergent adverse events.

Results: Of 107 patients randomized, 83 completed the study. The mean (SD) rate of rise of Hb during the first 6 weeks was - 0.052 (0.142) for placebo and + 0.200 (0.160), + 0.453 (0.256), and + 0.570 (0.240) for roxadustat 50-, 70-, and 100-mg TIW groups, respectively (p < 0.001). Response rate was 14.8% for placebo and 81.5%, 100%, and 100% for roxadustat TIW groups (p < 0.001). Change in Hb from baseline at weeks 18-24 was - 0.17 (0.61) for placebo and + 1.10 (0.71), + 1.33 (0.82), and + 1.55 (0.88) g/dL for roxadustat TIW groups (p < 0.001). No deaths or major adverse cardiac events occurred with roxadustat.

Conclusion: Roxadustat was well tolerated and effective in correcting Hb levels within 6 weeks in Japanese anemic NDD-CKD patients.

Trial registration: ClinicalTrials.gov: NCT01964196. Registered 15 October 2013 (retrospectively registered).

Funding: Astellas Pharma Inc.

Keywords: Anemia; CKD; Clinical trial; Hemoglobin; Nephrology; Roxadustat.

Fig. 1

Patient randomization and treatment protocol. Hb hemoglobin, QW once weekly, TIW three times weekly. ^aTo maintain blinding, patients took roxadustat QW and placebo, which was indistinguishable from roxadustat, twice weekly. ^bIn order to maintain blinding, dose adjustment and the second randomization by the web registration system were performed in the placebo arm, but in actuality did not occur

Fig. 2

Patient disposition. ^aDiscontinuation due to progressive disease requiring initiation of dialysis occurred in three patients [11.1%] in the 50-mg TIW group and one patient [3.7%] in the 100-mg TIW group. All four patients had baseline eGFR ≤ 10 mL/min/1.73 m². All four cases were considered to be consistent with the natural progression of disease and therefore unrelated to the study drug

Fig. 3

Rate of rise in hemoglobin from baseline during the fixed-dose period (6 weeks). *p < 0.001. Boxplots depict the interquartile range (box), mean (x), median (black bar), range (whiskers), and outliers (circles); rate of rise in Hb was calculated as the slope of a linear regression for each patient using all Hb data collected during the fixed-dose period. Data for the roxadustat TIW pooled group was the mean rate of rise in Hb for all roxadustat TIW-treated patients. Hb hemoglobin, TIW three times weekly

Fig. 4

Hemoglobin levels by week over the entire treatment period stratified by a dose during the fixed-dose period and b dosing frequency during the titration period. Data presented are mean ± standard deviation. Grayed area represents the Hb target range of 10–12 g/dL. FU4 follow-up week 4, QW once weekly, SCa screening assessment, SCp screening period, TIW three times weekly