Phase 3 Study of Roxadustat to Treat Anemia in Non–Dialysis-Dependant CKD

Abstract

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated safety and efficacy versus placebo in phase III trials in patients with anemia of chronic kidney disease (CKD) who were not on dialysis (NDD).Methods: This was a phase III, active-controlled, multicenter, partially randomized, open-label study in Japanese patients with NDD CKD. Patients who had used recombinant human erythropoietin or darbepoetin alfa (DA) before conversion were randomized to roxadustat or DA (comparative arms). Patients who had used epoetin beta pegol before conversion were allocated to roxadustat (reference arm). The primary endpoint was change in average hemoglobin (Hb) level from baseline during the evaluation period (Weeks 18-24). Longer term efficacy and safety were evaluated in roxadustat-treated patients over 52 weeks.Results: In this study, 334 patients were randomized/allocated to receive treatment (n). The estimated difference between the roxadustat (comparative) and DA (comparative) groups in the least squares mean of change of average Hb levels of Weeks 18 to 24 from baseline was -0.07 g/dl, with the lower limit of 95% confidence interval of -0.23 g/dl, thereby confirming the noninferiority of roxadustat to DA. Common treatmentemergent adverse events ($3% of patients in any treatment group) observed during the 24-week treatment period included nasopharyngitis, CKD, hyperkalemia, and hypertension. Conclusion:Roxadustat maintained Hb within 10 to 12 g/dl in NDD CKD patients and was noninferior to DA. The safety profiles observed in this study are consistent with previous studies performed in this patient population.

Two Phase 3 Studies on Ophthalmologic Effects of Roxadustat Versus Darbepoetin

“…Study 1517-CL-0310 26 was a multicenter, partially randomized (nonrandomized reference group is described subsequently), DA-controlled, open-label study conducted in Japan from January 2017 to March 2020 (ClinicalTrials.gov: NCT02988973 ). In this study, NDD patients with CKD previously treated with recombinant human erythropoietin or DA were randomized to initially receive roxadustat 3 times weekly for 52 weeks or DA once every 2 weeks for 24 weeks, whereas NDD patients with CKD who had previously used epoetin beta pegol were assigned to receive roxadustat 3 times weekly for 52 weeks (reference group); the reference group was not included in this ophthalmologic analysis ( Figure 1 b).…”

“…In phase 3 studies, roxadustat has been found to have efficacy and safety in achieving and maintaining Hb target levels in DD 20 , 21 , 22 , 23 and NDD 24 , 25 , 26 patients with CKD with anemia. Specifically, 2 Japanese phase 3 studies have revealed the efficacy of roxadustat in maintaining Hb within 10.0 to 12.0 g/dl in DD (study 1517-CL-0307) 20 and NDD 26 patients with CKD with anemia whose Hb levels were previously maintained with ESAs; in both studies, roxadustat was found to be noninferior to DA.…”

Current Status of Renal Anemia Pharmacotherapy—What Can We Offer Today

“…All published phase II trials indicate that HIF-PHI therapy is at least as efficacious as conventional ESA therapy in managing Hb levels in both nondialysis-dependent CKD (ND-CKD and dialysis-dependent (DD-CKD) patients [ 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ]. The meta-analysis of 26 randomized controlled trials involving 2804 patients with CKD comparing the use of HIF-PHIs versus ESAs or placebo in the treatment of renal anemia found HIF-PHIs superior to placebo and at least as efficacious as classic ESAs in the short term [ 5 ].…”

“…Regarding safety, HIFs also activate, additionally to EPO, a large number of genes, which can also cause beneficial effects. Potential clinical benefits of HIF-PHIs therapy include: achieving Hb target with a 5–17-fold lower plasma EPO levels relative to those receiving ESA; and a lipid-lowering effect, blood-pressure reduction, anti-inflammatory effects, protection from ischemic injuries, and protective effects with regard to CKD [ 5 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ]. Roxadustat and daprodustat are demonstrated to reduce triglyceride, total cholesterol, and low-density lipoprotein levels [ 62 , 63 , 69 , 71 ].…”

Randomized Study on the Efficacy of Standard Versus Low Roxadustat Dose for Anemia in Patients on Peritoneal Dialysis

“…[3][4][5][6][7] Several phase III clinical trials have verified the efficacy and safety of roxadustat as a therapy for anemia in nondialysis-dependent and dialysis-dependent patients. 5,[8][9][10][11] Of note, previous phase II and III trials indicated the dose-effect relationship of roxadustat and correction of anemia, 6,12 where Hb levels rapidly increased by approximately 10 g/l within the first 4 to 5 weeks with a weight-based initial dose, that is, 1.5 to 2 mg/kg 3 times per week. 6,7,13 This phenomenon in turn explained why the mean weekly dose of roxadustat was reduced after 4 weeks of treatment in some dialysis-dependent recipients with 100 to 110 g/l of Hb at baseline, indicating dose reduction due to Hb overshooting.…”