Roxadustat is more effective than placebo at correcting anemia in patients with chronic kidney disease (CKD) not on dialysis and is noninferior to epoetin alfa in treating anemia in patients on long-term dialysis, according to 2 new studies published in the New England Journal of Medicine by the same research team.
In a phase 3 trial, Nan Chen, MD, of Ruijin Hospital in China and colleagues randomly assigned 154 CKD patients not on dialysis to receive roxadustat—an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase enzymes—or placebo 3 times per week for 8 weeks. Mean Hb increased 1.9 g/dL with roxadustat and decreased 0.4 g/dL with placebo from a baseline value of 7.0 to 10.0 g/dL. Hb correction in CKD patients was maintained during an 18-week open label period. In the other trial, Dr Chen’s team randomly assigned 305 patients on hemodialysis or peritoneal dialysis previously treated with epoetin alfa for 6 weeks to receive epoetin alfa or roxadustat 3 times per week for 26 weeks. Mean Hb levels rose 0.7 g/dL in the roxadustat group and 0.5 g/dL in the epoetin arm from a baseline value of 10.4 g/dL, demonstrating noninferiority.
Hepcidin declined more with roxadustat than epoetin in dialysis patients (30.2 vs 2.3 ng/mL) and CKD patients (56 vs 15.1 ng/mL). Dialysis patients’ iron profile improved more with roxadustat. Compared with epoetin, roxadustat maintained serum iron, increased transferrin by 0.43 g/L more, and attenuated decreases in transferrin saturation by 4.2 more percentage points. Parenteral iron was not permitted in either trial except as rescue therapy.
Roxadustat also improved cholesterol levels. At week 27 of the dialysis trial, roxadustat decreased total cholesterol and low-density lipoprotein by 22 and 18 mg/dL, respectively, more than epoetin. In the CKD trial, roxadustat reduced total cholesterol by 40.6 mg/dL compared with just 7.7 mg/dL with placebo.
With respect to safety, roxadustat was associated with several adverse events. In the dialysis trial, hyperkalemia (7.4% vs 1.0%) and upper respiratory infection (18.1% vs 11.0%) occurred more frequently with roxadustat, whereas hypertension occurred more frequently with epoetin (12.3% vs 16.0%). In the CKD trial, hyperkalemia (16% vs 8%) and metabolic acidosis (12% vs 2.0%) occurred more frequently with roxadustat. According to Dr Kaplan, it is prudent to exercise caution in using roxadustat in patients predisposed to hyperkalemia.
Among the notable limitations, the trials, funded by FibroGen, the maker of roxadustat, included only Han Chinese patients. Results could possibly differ for other populations. The trials were also smaller and shorter that the CHOIR and TREAT trials evaluating ESAs. Two international phase 3 trials of roxadustat now underway (NCT02273726 and NCT01750190) should provide additional useful data. An important question is whether roxadustat permits Hb correction to normal levels.
Beyond increasing erythropoietin, HIF prolyl hydroxylase inhibitors reduce inflammation and improve iron handling by decreasing hepcidin, Joshua Kaplan, MD, of Rutgers Medical School in New Jersey, explained in an accompanying editorial. “The maintenance of serum iron levels in the roxadustat group, as compared with decreased iron levels in the erythropoietin group, corresponds with the effect of roxadustat on hepcidin and subsequent increase of ferroportin, allowing increased access to enteral iron and macrophage iron stores.”
Roxadustat might be appropriate for patients with inflammation and hyporesponsiveness to erythropoiesis stimulating agents, he added.
“If HIF prolyl hydroxylase inhibitors fulfill their promise and facilitate normalization of hemoglobin levels in patients with chronic kidney disease and reduce cardiovascular morbidity related to anemia without the increased risks that have been seen in trials of erythropoietin-stimulating agents, there might ultimately be a revolution in the treatment of anemia of chronic kidney disease,” Dr Kaplan wrote.
Chen N, Hao C, Liu BC, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. [published online July 24, 2019]. N Engl J Med.
Chen N, Hao C, Liu BC, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis [published online July 24, 2019]. N Engl J Med.
Kaplan J. Roxadustat and anemia of chronic kidney disease [published online July 24, 2019]. N Engl J Med.