Roxadustat has proven noninferior to darbepoetin alfa in achieving hemoglobin (Hb) correction in patients with non-dialysis-dependent chronic kidney disease (CKD) patients and Hb maintenance in patients on hemodialysis (HD), investigators announced in an oral session at the European Renal Association-European Dialysis and Transplant Association 2020 virtual congress and, separately, reported in the Journal of the American Society of Nephrology.
Roxadustat is a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI). In the phase 3 DOLOMITES study (NCT02021318), 616 patients with stage 3-5 CKD who had Hb levels of 10.5 g/dL or less were randomly assigned to receive roxadustat or darbepoetin alfa, an erythropoiesis stimulating agent (ESA). Over 24 weeks, a significantly greater percentage of roxadustat than darbepoetin alfa recipients (89.5% vs 78.0%) achieved the primary end point of an Hb level of 11 g/dL or higher (along with a Hb increase of 2.0 g/dL or more in patients with baseline Hb of 8.0 g/dL or less or a Hb increase of 1 g/dL or more in patients with baseline Hb higher than 8 g/dL), Jonathan Barratt, PhD, of the University of Leicester in the United Kingdom, reported.
In addition, roxadustat proved superior to darbepoetin alfa in decreasing low-density lipoprotein cholesterol with a least square mean (LSM) difference of -0.403 mmol/L and in increasing time to first intravenous (IV) iron use. Roxadustat use was significantly associated with a 54% decreased likelihood of requiring IV iron compared with darbepoetin alfa treatment. Roxadustat was noninferior to darbepoetin alfa in measures of hypertension risk, including mean arterial pressure change from baseline to weeks 12-28 with a LSM difference of -0.372 mm Hg and time to development of hypertension.
The most common adverse events in both groups included hypertension (28.4 vs 37.3 per 100 patient exposure years, respectively), end-stage renal disease (24.3 vs 24.3 per 100 patient exposure years), decline in estimated glomerular filtration rate (12.1 vs 13.0 per 100 patient exposure years), and peripheral edema (12.1 vs 12.6 per 100 patient exposure years).
A preliminary analysis of major adverse cardiovascular events (MACE) and MACE plus hospitalization for unstable angina or congestive heart failure (MACE+) found that roxadustat use was associated with a nonsignificant 19% and 10% decreased risk of these outcomes, respectively, compared with darbepoetin alfa treatment.
Of the original cohort, 89 patients completed a full 2 years of treatment with roxadustat.
“The DOLOMITES study results demonstrate the ability of roxadustat to correct and maintain hemoglobin levels in people with CKD anemia not on dialysis for up to 2 years,” Dr Barratt stated in a news release.
In the second Japanese study (NCT02952092), 151 HD patients were randomly assigned to roxadustat and 152 to darbepoetin alfa to maintain Hb levels between 10 and 12 g/dL. Mean Hb at weeks 18 to 24 was 10.99 g/dL in roxadustat recipients with an estimated difference of -0.02 g/dL compared with darbepoetin alfa recipients, Tadao Akizawa, MD, PhD, of Showa University School of Medicine, in Tokyo, and colleagues reported. Serum iron, ferritin, and transferrin saturation (TSAT) remained clinically stable with roxadustat, whereas transferrin and total iron binding capacity increased through week 4 before stabilizing.
Adverse events were consistent with previous reports and most commonly included nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. New or worsening retinal hemorrhage occurred in similar proportions of both groups: 32.4% with roxadustat vs 36.6% with darbepoetin alfa. There were no changes in retinal thickness. This study was not adequately powered to assess cardiovascular outcomes.
“These data confirm that oral roxadustat is a valid alternative to injectable erythropoiesis-stimulating agents for dialysis-dependent CKD anemia,” Dr Akizawa’s team stated.
Disclosure: Both clinicals trial were supported by Astellas Pharma. Please see the original references for a full list of authors’ disclosures.
Barratt J, Andrić B, Tataradze A, et al. Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis: A Phase 3, Randomised, Open-Label, Active-Controlled Study. Nephrol Dial Transplant. 35(3). doi: 10.1093/ndt/gfaa140.MO001 Presented at the European Renal Association-European Dialysis and Transplant Association 2020 virtual congress. Abstract MO001.
FibroGen announces new roxadustat data presented at 2020 ERA-EDTA virtual congress [news release]. Biospace; June 8, 2020.
Akizawa T, Iwasaki M, Yamaguchi Y, Majikawa Y, Reusch M. Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients With Anemia on Hemodialysis in Japan. J Am Soc Nephrol. doi: 10.1681/ASN.2019060623