Safety and Efficacy of Vadadustat Once Daily and Three Times Weekly in Patients With Dialysis-Dependent CKD With Anemia

Key Points In this phase 3b, noninferiority trial, vadadustat once daily was noninferior to darbepoetin alfa (DA) in the correction and maintenance of hemoglobin in dialysis-dependent CKD. Vadadustat three times weekly treatment resulted in similar changes in mean hemoglobin levels compared with vadadustat once daily, but was not noninferior to DA. The safety profiles of vadadustat once daily and vadadustat three times weekly were comparable with that of DA. Background Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia in CKD. This study investigated the safety and efficacy of once-daily and three-times-weekly dosing in patients with dialysis-dependent CKD compared with darbepoetin alfa (DA). Methods This phase 3b, randomized (1:1:1; vadadustat once daily [starting dose: 300 or 450 mg], vadadustat three times weekly [starting dose: 600 or 750 mg], DA), open-label, active-controlled, noninferiority trial included conversion (weeks 0–20) and maintenance (weeks 20–52) periods. Primary and secondary efficacy end points were mean change in hemoglobin from baseline during the primary evaluation period (PEP, weeks 20–26) and secondary evaluation period (weeks 46–52). Other end points included proportion of patients requiring erythropoiesis-stimulating agent (ESA) rescue (hemoglobin <9.5 g/dl or with increases in dose ≥50% or ≥100% in the DA group). Safety end points included treatment-emergent adverse events (AEs) and serious AEs. Results The least-squares (LS) mean treatment difference between vadadustat once daily and DA from baseline to PEP was −0.27 g/dl (95% confidence interval [CI], −0.55 to 0.01); the lower bound met the noninferiority threshold (−0.75 g/dl). The LS mean treatment difference between vadadustat three times weekly and DA from baseline to PEP was −0.53 g/dl (95% CI, −0.80 to −0.25), which did not meet the lower bound noninferiority threshold. The LS mean change from baseline to the secondary evaluation period between DA and vadadustat once daily was −0.40 (95% CI, −0.79 to −0.02) and for vadadustat three times weekly was −0.42 (95% CI, −0.81 to −0.02). The proportion of patients who received ESA rescue during weeks 2–52 was higher in the DA group than vadadustat groups. Similar treatment-emergent AEs and treatment-emergent serious AEs were observed across groups. Conclusions Vadadustat once daily, but not three times weekly, was noninferior to DA in the correction and maintenance of hemoglobin in patients with dialysis-dependent CKD converted from an ESA; safety profiles were similar across groups. Clinical Trial registry name and registration number: EudraCT 2019-004851-36/ClinicalTrials.gov identifier: NCT04313153.