Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis

N Engl J Med. 2019 Sep 12;381(11):1011-1022. doi: 10.1056/NEJMoa1901713. Epub 2019 Jul 24.

Abstract

Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis.

Methods: In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values.

Results: A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group.

Conclusions: Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Equivalence Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Analysis of Variance
  • Anemia / drug therapy*
  • Anemia / etiology
  • Cholesterol / blood
  • Double-Blind Method
  • Epoetin Alfa / adverse effects
  • Epoetin Alfa / therapeutic use*
  • Female
  • Glycine / adverse effects
  • Glycine / analogs & derivatives*
  • Glycine / therapeutic use
  • Hematinics / adverse effects
  • Hematinics / therapeutic use*
  • Hemoglobins / analysis*
  • Humans
  • Hyperkalemia / chemically induced
  • Hypertension / chemically induced
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Isoquinolines / adverse effects
  • Isoquinolines / therapeutic use*
  • Male
  • Middle Aged
  • Renal Dialysis
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / complications*
  • Renal Insufficiency, Chronic / therapy

Substances

  • FG-4592
  • Hematinics
  • Hemoglobins
  • Isoquinolines
  • Epoetin Alfa
  • Cholesterol
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Glycine

Associated data

  • ClinicalTrials.gov/NCT02652806