Mo001roxadustat for the Treatment of Anaemia in Chronic Kidney Disease Patients Not on Dialysis: A Phase 3, Randomised, Open-Label, Active-Controlled Study

Abstract

Background and Aims Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anaemia in patients (pts) with chronic kidney disease (CKD). Efficacy and safety of roxadustat compared with darbepoetin alfa (DA) for the treatment of anaemia in CKD pts not on dialysis (NDD) was assessed in a randomised, open-label, active-controlled phase 3 study. Results from a protocol-specified interim analysis, performed after pts had either completed ≥36 weeks of treatment or had withdrawn from the study, are presented here. Method This study (CL-0610) enrolled pts with NDD CKD stages 3-5 and anaemia (haemoglobin [Hb] ≤10.5 g/dL) and randomised them to receive roxadustat or DA. Following prescribed initial doses (weight-based), dose adjustments were permitted, with the goal of correcting and maintaining Hb. The primary endpoint was Hb response, defined as Hb ≥11.0 g/dL and an Hb increase from baseline (BL) of ≥1.0 g/dL in pts with BL Hb >8.0 g/dL, or an increase of ≥2.0 g/dL in pts with BL Hb ≤8.0 g/dL, during the first 24 weeks of treatment without rescue therapy. Key secondary endpoints included change in serum lipids, time to first IV iron use, change in mean arterial pressure (MAP), and occurrence of hypertension. Noninferiority of roxadustat to DA was declared if the lower bound of the two-sided 95% confidence interval (CI; roxadustat – DA) for change in Hb was >-0.15. Adverse events (AEs) were assessed across the study and are presented as events/100 patient exposure years (PEY) unless otherwise specified. The full analysis set (FAS) included pts who received ≥1 dose of study drug and had ≥1 post-dose Hb assessment. The per protocol set (PPS) included FAS pts who did not meet exclusion criteria. The safety analysis set (SAF) included pts who received ≥1 dose of study drug. Results As of 15 June 2018, 616 pts were randomised to receive roxadustat (n=323) or DA (n=293); of these 616 pts, 395 pts (roxadustat, n=194; DA, n=201) were still receiving treatment and 89 pts had completed ≥2 years of treatment (roxadustat, n=55; DA, n=34). In the PPS, 89.5% (n=256) of roxadustat pts responded in the first 24 weeks compared with 78.0% (n=213) of DA pts, for a difference of 11.51% (95% CI: 5.66%, 17.36%), thereby establishing roxadustat’s noninferiority to DA. Noninferiority of roxadustat to DA was also demonstrated for MAP and time to occurrence of hypertension. In the FAS, superiority of roxadustat to DA was demonstrated for low-density lipoprotein (LDL) and time to first IV iron use. (Table) In the SAF, overall incidence of AEs was comparable between roxadustat and DA (85.8% and 84.6%, respectively). Conclusion This analysis demonstrates that roxadustat was noninferior to DA in correction of Hb levels during the first 24 weeks of treatment in pts with NDD CKD stages 3-5 and anaemia. Safety profiles were comparable between groups. Final analysis of this study’s data will be presented at the congress.

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

“…89 Preliminary data from the larger international, doubleblind, placebo-controlled ALPS (n ¼ 594), 90 ANDES (n ¼ 922), 91 and OLYMPUS (n ¼ 2781) 92 trials indicated that roxadustat was efficacious in correcting and maintaining Hb levels over 52 weeks; and in a preliminary report from the open-label, active-controlled DOLOMITES trial (n ¼ 616), roxadustat was noninferior to darbepoetin alfa in providing Hb response over 24 weeks. 93 Preliminary data from Japanese studies reported that daprodustat was noninferior to epoetin beta pegol (n ¼ 299), 15 whereas enarodustat (n ¼ 216), 78 molidustat (n ¼ 161 and 164), 86,87 and vadadustat (n ¼ 304) 19 were noninferior to darbepoetin alfa for maintaining target Hb levels. In the large global PRO2TECT trial, vadadustat achieved noninferiority compared with darbepoetin alfa in both the correction (n ¼ 1751) and the conversion (n ¼ 1725) arms.…”

“…Dose-dependent increases in Hb levels were observed in phase 2 studies of orally administered daprodustat, [100][101][102] desidustat, 103 enarodustat, 104 molidustat, 80,105 roxadustat, [106][107][108][109] and vadadustat [110][111][112] over 4-to 30-week treatment periods in recombinant human EPO-naïve patients or patients with prior exposure to ESA. Of the HIF-PHIs in development, phase 3 data in NDD CKD patients are reported for daprodustat, 15 enarodustat, 78 molidustat, 86,87 roxadustat, 23,[88][89][90][91][92][93] and vadadustat 19,94 (Table 2). Roxadustat, VH Haase: HIF-PH inhibitors for anemia of CKD c l i n i c a l i n v e s t i g a t i o n c l i n i c a l i n v e s t i g a t i o n VH Haase: HIF-PH inhibitors for anemia of CKD orally administered 3 times weekly, effectively corrected Hb levels in a small double-blind, placebo-controlled phase 3 study in China (n ¼ 154; 8-week duration) 23 and in a 2-arm, randomized, open-label, noncomparative study in Japan (n ¼ 99; 24-week duration), 88 and was noninferior to darbepoetin alfa in preliminary results from a 52-week, randomized, open-label, active-comparator study in Japan (n ¼ 262).…”

Anemia in Chronic Kidney Disease: From Pathophysiology and Current Treatments, to Future Agents

“…The results of the DOLOMITES trial were presented i in the past ERA-EDTA congress in June 2020 ( 116 ) and in the 2020 ASN Annual Meeting ( 117 ). This phase 3, randomized, open-label, active-controlled study evaluated the efficacy and safety of roxadustat compared to DA in the treatment of anemia in NDD- CKD patients.…”

Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin

“…Daprodustat (GSK1278863) and vadadustat (AKB-6548) are also now approved in Japan for the treatment of anemia in patients with DD-CKD or NDD-CKD [ 123 , 124 ]. All three HIF-PH inhibitors effectively stimulate EPO production in patients with anemia of CKD, providing dose-dependent increases in Hb and reductions in hepcidin levels, and thus improving total iron binding capacity (TIBC) [ 35 , 90 – 93 , 96 – 98 , 103 , 125 – 127 ].…”

“…In these studies, roxadustat was also associated with a reduced risk of rescue therapy (ESA or IV iron) and RBC transfusion [ 98 ] and reduced hepcidin levels compared with placebo (between group difference −50 ng/ml) [ 96 ]. Interim data from a phase 3 study showed that roxadustat was noninferior to darbepoetin alfa regarding Hb response in NDD-CKD patients [ 125 ]. Preliminary data from a Japanese phase 3 study showed that vadadustat was as effective as darbepoetin alfa in maintaining Hb levels in both ESA-naïve and ESA-converted NDD-CKD patients with anemia [ 126 ].…”