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Chinese studies show effectiveness of roxadustat for CKD, ESRD
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Two phase 3 trials in a Chinese patient population with kidney disease and anemia showed use of the oral hypoxia-inducible factor prolyl hydroxlase inhibitor roxadustat was superior to placebo in increasing hemoglobin levels in patients not on dialysis and was noninferior to erythropoietin in patients undergoing dialysis.
In the trial with patients on dialysis, the researchers randomly assigned — with a 2:1 ratio — patients with ESKD who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with erythropoietin (epoetin alfa) for at least 6 weeks. Patients either received 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,” the authors wrote.
Patients in both groups had doses adjusted to reach a hemoglobin level of 10 to 12 grams per deciliter. Of the 305 patients who underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), 256 patients (162 and 94, respectively) completed the 26-week trial.
“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 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], 0.02 to 0.5),” the authors wrote. “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 g 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 compared to the epoetin alfa group, but “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,” the authors wrote.
In the second trial for patients not on dialysis, “roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis,” the authors wrote. In this trial using 29 sites in China, the researchers randomly assigned 154 patients with chronic kidney disease to receive roxadustat or placebo three times a week for 8 weeks.
“All the patients had a hemoglobin level of 7 [grams] to 10 [grams] per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9,” the authors wrote.
During the primary-analysis period, the mean change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group, the authors reported. The mean reduction from baseline in the hepcidin level was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. Total cholesterol levels were also lower in the roxadustat group.
“Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open label period,” the authors wrote.
In an editorial accompanying the papers, Joshua Kaplan, MD, wrote that the increase in hyperkalemia in both studies needs further attention.
“Both trials showed a higher risk of hyperkalemia with roxadustat than with the control (epoietin alfa or placebo). The pathophysiological mechanism by which [hypoxia-inducible factor] HIF prolyl hydroxylase inhibitors may cause hyperkalemia is unclear, and hyperkalemia has not been reported as an adverse event in phase 2 trials of other HIF prolyl hydroxylase inhibitors, so hyperkalemia may be an off-target effect of roxadustat rather than a class effect ... Given the increased incidence of hyperkalemia that has been reported in multiple trials of this agent, it seems prudent to exercise caution in using this agent in patients who have a predisposition to hyperkalemia.”
Kaplan added that the Chinese population tested in the trials may limit application to patient groups in other countries. “We should keep in mind that the findings in Han Chinese patients, who may have unique genetic factors, may render extrapolation to other populations unwise,” Kaplan said. “Furthermore, these phase 3 trials are smaller, by a factor of 3 to 10, and much shorter, by a factor of 3 to 4, than the CHOIR and TREAT trials and other studies of erythropoietin-stimulating agents. Can this agent treat patients with erythropoietin-stimulating agent–resistant and hyporesponsive anemia more effectively and more safely than the current treatment using erythropoietin and iron?” –by Mark E. Neumann
Disclosures: The clinical trials were funded by FibroGen and FibroGen [China] Medical Technology. Chen and Kaplan report no relevant financial disclosures. Other authors from both studies reported that they received grants from FibroGen during the study or have received personal fees from FibroGen, outside the submitted work. Please see the complete studies for relevant financial disclosures.
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