Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease

Abstract

Background: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD.

Methods: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability.

Results: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration.

Conclusions: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients.

Keywords: Anemia; Chronic kidney disease; Clinical trials; Erythropoietin; Kidney disease.

Fig. 1

Effect of trial treatment on hemoglobin (Hb) at week 6 (modified intent to treat population). For patients who underwent dose reduction during the trial, end-of-treatment Hb was defined as the Hb immediately preceding dose reduction. Five (26%) of the patients in the 630 mg vadadustat treatment group, 2 (12%) of patients in the 500 mg vadadustat treatment group and 2 (11%) of patients in the 240 mg group underwent protocol-defined dose reductions by week 4. Imputation was not performed for missing values, and missing values were excluded from analysis. a Mean changes in Hb (±SEM) compared to baseline. A one-way analysis of variance test was performed with change from baseline as the dependent variable and treatment group as the independent variable. * p < 0.05 for comparisons with baseline. †p < 0.05 for comparisons with placebo. b Proportion of trial patients who achieved increases in Hb ≥1 g/dL at week 6 compared with baseline.

Fig. 2

Observed mean hemoglobin (Hb) concentration over the trial period during administration of vadadustat or placebo (modified intent to treat population). Data are expressed as the mean ± SEM Hb value at each time point. * p < 0.05 for comparisons with baseline. † p < 0.05 for comparisons with placebo.

Fig. 3

Observed mean ferritin concentration and total iron binding capacity (TIBC) over the trial period during administration of vadadustat or placebo (modified intent to treat population). Data are expressed as the mean ± SEM at each time point. a Mean change in ferritin concentration (±SEM) compared to baseline. b Mean change in TIBC compared to baseline. c Mean change in hepcidin concentration compared to baseline. * p < 0.05 for comparisons with baseline. † p < 0.05 for comparisons with placebo.