WASHINGTON—Roxadustat increases hemoglobin levels and decreases the need for intravenous (IV) iron to a greater extent than epoetin alfa in dialysis patients with anemia, according to study data presented at the American Society of Nephrology’s 2019 Kidney Week conference. Roxadustat treatment also demonstrated superior cardiovascular (CV) safety in this population.
Moreover, roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and improves iron absorption and utilization, proved efficacious and safe in non-dialysis-dependent chronic kidney disease (NDD-CKD) compared with placebo, significantly raising hemoglobin levels and decreasing the risk of requiring rescue therapies such as red blood cell transfusions.
“Roxadustat is effective in treating anemia in CKD and dialysis-dependent patients, and is safe and appears to be safer than ESAs [erythropoiesis stimulating agents] in incident dialysis patients,” said Robert Provenzano, MD, who reported the findings of a pooled analysis of multiple phase 3 trials during an oral presentation. He was the lead investigator of one of the trials (HIMALAYAS). In addition, roxadustat slowed the decline in estimated glomerular filtration rate in patients with chronic kidney disease (CKD) stage 3 and 4. The drug’s efficacy was independent of iron status or inflammation, Dr Provenzano said.
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Among 3917 dialysis patients (1960 randomly assigned to roxadustat and 1957 to epoetin alfa), the mean hemoglobin change from baseline to an average over weeks 28 to 52 (the primary end point) was +1.21 g/dL for roxadustat-treated patients compared with +0.95 g/dL in the epoetin alfa group, a significant +0.26 g/dL difference.
The proportion of patients requiring transfusion was significantly smaller in the roxadustat than epoetin alfa arm (9.5% vs 12.8%). The pooled analysis of NDD-CKD patients, which included 2386 patients randomly assigned to roxadustat and 1884 to placebo, revealed a mean hemoglobin change from baseline to an average over weeks 28 to 52 of +1.85 g/dL in the roxadustat group compared with +0.13 g/dL in the placebo arm, with an 81% decreased risk of requiring rescue therapy such as transfusion, intravenous iron, or ESA.
Dr Provenzano pointed out that the use of placebo as a comparator is important given the limited proportion of CKD patients currently treated with ESAs because of the known CV risks associated with these medications and the black box warnings placed on these agents in the past decade. The roxadustat phase 3 program is powered to evaluate for noninferiority in this patient population, and results show no increased risk compared with placebo or nontreatment of anemia, he said.
The pooled analysis also looked at the incidence of major adverse cardiac events, or MACE (death, myocardial infarction, or stroke), and MACE in addition to heart failure or unstable angina requiring hospitalization (MACE+). In the dialysis population, roxadustat recipients had a significant 16% decreased risk of MACE+ compared with epoetin alfa patients. Among 1526 incident dialysis patients, roxadustat-treated patients had significant 30% and 34% decreased risks of MACE and MACE+, respectively, compared with patients treated with epoetin alfa. Among NDD-CKD patients, the analysis found no significant difference between the group with regard to MACE or MACE+.
The HIMALAYAS trial included 1043 incident dialysis patients (522 roxadustat and 521 epoetin alfa). The mean change from baseline to the average over weeks 28 to 52 was +2.57 g/dL in the roxadustat arm and +2.36 g/dL in the epoetin alfa arm. Results showed that roxadustat was noninferior, and indeed superior, to epoetin alfa with regard to the primary efficacy end point, said Dr Provenzano, Associate Clinical Professor of Medicine at Wayne State University School of Medicine in Detroit. In addition, roxadustat-treated patients required less iron while maintaining iron repletion almost identical to the epoetin alfa group. Roxadustat also was noninferior to epoetin alfa in patients who were iron depleted or inflamed at baseline.
Steven Fishbane, MD, Professor of Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, New York, presented findings from the ROCKIES trial, which included 2106 prevalent dialysis patients with anemia (1051 on roxadustat and 1055 on epoetin alfa), and the OLYMPUS trial, which included 2761 anemic patients with NDD-CKD (1384 on roxadustat and 1377 on placebo). The pooled analysis included data from these trials. In the ROCKIES trial, the mean hemoglobin change from baseline to an average over weeks 28 to 52 was significantly higher in the roxadustat group compared with epoetin alfa recipients in the overall cohort (+0.77 vs +0.68 g/dL) and among patients with elevated baseline high-sensitivity C-reactive protein (hs-CRP) (+0.80 vs +0.59 g/dL).
In addition, roxadustat-treated patients required significantly less monthly IV iron than epoetin alfa recipients from week 36 to the end of the study (58.7 vs 91.4 mg). The proportion of patients who required red blood cell (RBC) transfusions was similar between the study arms.
In the double-blind OLYMPUS trial, roxadustat significantly increased hemoglobin levels compared with placebo regardless of iron-repletion status or inflammation, Dr Fishbane said.
The mean change in hemoglobin from baseline to the average over weeks 28 to 52 for the overall study population was +1.75 g/dL among roxadustat-treated patients compared with +0.40 g/dL for placebo recipients. Compared with placebo, roxadustat decreased the risk of requiring rescue therapy by 74%, including a 63% decreased risk of RBC transfusion, 59% decreased risk of IV iron use, and 87% decreased risk of ESA use.
