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

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.