According to results from a phase III trial, roxadustat increased hemoglobin levels and hemoglobin response rates, compared with placebo, in patients with anemia and chronic kidney disease (CKD) who were not undergoing dialysis. The results of the study, which were published in the New England Journal of Medicine, also showed that roxadustat was associated with reduced levels of cholesterol and hepcidin, a key regulator of iron absorption.
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that regulates iron metabolism and stimulates erythropoiesis, the authors, led by Nan Chen, MD, of Shanghai Jiao Tong University School of Medicine, explained.
In earlier trials of patients with CKD-related anemia, “roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis.” This phase III trial, which was conducted at 29 sites in China, compared the safety and efficacy of roxadustat with placebo in patients with stage 3 to 5 CKD.
Eligible participants were be-tween the ages of 18 and 75, not undergoing dialysis, who had not received erythropoiesis-stimulating agents in at least five weeks and had a mean hemoglobin level of 7 to <10 g/dL at the time of screening. One hundred and fifty-four patients were randomized; two patients did not receive a trial regimen and one was lost to follow-up after one dose of placebo, bringing the intention-to-treat population to 151.
In the initial double-blind phase of the trial, participants were randomized in a 2:1 ratio to receive eight weeks of either:
- roxadustat (n=87; mean age = 54.7±13.3)
- placebo (n=44; mean age = 53.2±13.1)
Per study protocol, patients started on either 70 or 100 mg of roxadustat (based on body weight) three times a week. Dose was escalated every four weeks to maintain a hemoglobin level of 10 to 12 g/dL. Placebo was administered in the same manner. A total of 131 patients (87 in the roxadustat group and 44 in the placebo group) completed the eight-week trial.
The initial period was followed by an 18-week open-label phase in which all patients received roxadustat. Blood transfusion, intravenous iron, and erythropoiesis-stimulating agents were offered to patients with a hemoglobin level <8 g/dL and those with a level <9 g/dL who had a confirmed decrease of >1 g/dL from baseline.
At baseline, patients in the roxadustat group had a mean hemoglobin level of 8.9±0.8 g/dL and patients in the placebo group had a mean hemoglobin level of 8.9±0.7 g/dL. In the roxadustat group, mean total cholesterol level was 172.8±45.8 mg/dL in the roxadustat group and 181.4±49.0 mg/dL in the placebo group.
The mean change in hemoglobin level from baseline to weeks 7 through 9 (the study’s primary endpoint) was significantly greater in the roxadustat group compared with the placebo group, with an increase of 1.9±1.2 g/dL versus a decrease of 0.4±0.8 g/dL (p<0.001).
The percentage of patients who experienced a hemoglobin response (defined as an increase of ≥1.0 g/dL from baseline) also was higher in the roxadustat group. By week 9, 84% of patients in the roxadustat group experienced a response, compared with no patients in the placebo group (p value not provided).
Roxadustat also was associated with a greater reduction in cholesterol levels, the authors reported. At week 9 of the randomized phase, total cholesterol had decreased 40.6 mg/dL from baseline in the roxadustat group and 7.7 mg/dL for those taking placebo (p value not provided).
In the open-label phase, in which all patients received roxadustat, hemoglobin levels remained stable among those who initially received the study drug, with an overall increase from baseline that remained at 1.9±1.3 g/dL by weeks 23 through 27. Crossing over to roxadustat also appeared to improve hemoglobin levels for those initially receiving placebo: Mean hemoglobin levels increased from baseline by 2.0±1.5 g/dL.
In this phase III trial, roxadustat increased hemoglobin levels and hemoglobin response rates, and was associated with reduced levels of cholesterol and hepcidin.
In the entire safety population (comprising 152 patients who received the trial regimen), 68% of patients in the roxadustat group and 75% in the placebo group reported at least one adverse event (AE).
The most common AEs were:
- hyperkalemia: 16 (16%) in the roxadustat group and 4 (8%) in the placebo group
- metabolic acidosis: 12 (12%) and 1 (2%)
Serious AEs were reported in 9% of patients taking roxadustat, versus 12% of patients in the placebo group. In the roxadustat group, serious AEs included hyperkalemia, lung infection, and gastrointestinal hemorrhage; in the placebo group, these included anemia, coronary artery disease, and renal impairment. No deaths were reported during the randomized phase, while two patients died during the open-label phase.
Potential limitations of this study include its small sample size, short trial duration, and abbreviated blinding period. It also is not known whether the trial drug is effective in the setting of other causes of chronic anemia. Given the improvements in hemoglobin, cholesterol, and hepcidin levels, the authors concluded that roxadustat should be evaluated in larger, international phase III studies.
The authors report relationships with FibroGen and FibroGen (China) Medical Technology Development, which supported this trial.
Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med. 2019;381:1001-10.