Clinical Pearls & Morning Reports
Published September 11, 2019
Chronic kidney disease is a global public health challenge that affects approximately 10% of the population worldwide, including 120 million people in China. Chen et al. conducted a phase 3 trial in China that evaluated roxadustat as treatment for anemia in patients with chronic kidney disease who were not undergoing dialysis. Read the Original Article here.
Q: What is roxadustat?
A: Roxadustat is a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that stabilizes HIF-α subunits, which results in increased HIF transcriptional activity. Increased transcriptional activity leads to functional activation of early-response target genes encoding proteins such as erythropoietin, erythropoietin receptor, enzymes of heme biosynthesis, and proteins that promote iron absorption and transport, which results in coordinated erythropoiesis.
Q: In the trial by Chen et al., did roxadustat increase the hemoglobin level in patients with chronic kidney disease who were not undergoing dialysis?
A: The design of the trial by Chen et al. called for an initial 8-week, double-blind, placebo-controlled phase in which the authors compared roxadustat with placebo. After the initial phase, all the patients who continued in the trial received roxadustat during an 18-week open-label phase. The primary efficacy analysis showed a significantly larger increase in the hemoglobin level from baseline over weeks 7 to 9 in the roxadustat group than in the placebo group (an increase of 1.9±1.2 g per deciliter vs. a decrease of 0.4±0.8 g per deciliter). Other hemoglobin end points, such as the percentage of patients who had a hemoglobin response (i.e., an increase of ≥1.0 g per deciliter from baseline) or who did not receive rescue therapy, were greater in the roxadustat group than in the placebo group. After the initial randomized phase of the trial, patients who had initially received roxadustat maintained stable hemoglobin levels during the open-label phase.
A: The authors found that in addition to the erythropoietic effects of roxadustat, the drug was associated with reduced levels of hepcidin and cholesterol. In patients with anemia who have a high hepcidin level, a reduction is typically associated with greater iron availability. At week 9, the reduction from baseline in the hepcidin level was 56.14±63.40 ng per milliliter and 15.10±48.06 ng per milliliter, respectively, for a between-group difference of –49.77 ng per milliliter (95% confidence interval [CI], –66.75% to –32.79). At week 9, the decrease in the total cholesterol level was 40.6 mg per deciliter (1.0 mmol per liter) in the roxadustat group and 7.7 mg per deciliter (0.2 mmol per liter) in the placebo group, for a between-group difference of –32.9 mg per deciliter (–0.9 mmol per liter; 95% CI, –1.1 to –0.6).
A: Among patients in the roxadustat group, the serum iron level was clinically stable during the randomized phase and did not differ significantly from the level in the placebo group, despite robust erythropoiesis. The authors speculate that the stability of serum iron levels in the roxadustat group may have been driven by reductions in hepcidin levels, which permitted the gut absorption of iron and improved the release of macrophage iron onto transferrin. Hepcidin, a key regulator of iron absorption and mobilization from hepatocytes and macrophages, is down-regulated by hypoxia and HIF stabilization, which increases the synthesis of iron transport proteins and intestinal iron absorption. Maintenance of total serum iron levels permits adequate iron delivery and avoidance of functional iron deficiency.