Phase 3 Randomized Study Comparing Vadadustat with Darbepoetin Alfa for Anemia in Japanese Patients with Nondialysis-Dependent CKD

Significance Statement Hypoxia-inducible factor prolyl hydroxylase inhibitors have been shown in clinical trials to increase hemoglobin levels via the production of endogenous erythropoietin. Vadadustat, an oral agent in this drug class, is an alternative to erythropoiesis-stimulating agents for the treatment of CKD-related anemia. This appears to be the first phase 3 randomized controlled trial to demonstrate noninferiority of vadadustat to darbepoetin alfa for the treatment of anemia in Japanese patients with nondialysis-dependent CKD. In participants receiving vadadustat, mean hemoglobin increased to the target range (11.0–13.0 g/dl) and was within this range up to week 52. Vadadustat was generally well tolerated over 52 weeks of treatment and no major safety concerns were identified. These findings suggest that vadadustat may be a potential treatment for anemia in patients with nondialysis-dependent CKD. Background Standard care for treating anemia in patients with CKD includes use of erythropoiesis-stimulating agents, which sometimes involves increased risks of cardiovascular morbidity and mortality. Previous studies in patients with anemia and nondialysis-dependent CKD (NDD-CKD) found significantly elevated hemoglobin levels with use of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, compared with placebo. Methods In this phase 3, open-label, active-controlled noninferiority trial, we randomized 304 Japanese adults with anemia in NDD-CKD (including erythropoiesis-stimulating agent users and nonusers) to oral vadadustat or subcutaneous darbepoetin alfa for 52 weeks. The primary efficacy end point was average hemoglobin at weeks 20 and 24. Safety data included adverse events (AEs) and serious AEs. Results A total of 151 participants received vadadustat and 153 received darbepoetin alfa. Least squares mean of the average hemoglobin at weeks 20 and 24 was 11.66 (95% confidence interval [95% CI], 11.49 to 11.84) g/dl for vadadustat and 11.93 (95% CI, 11.76 to 12.10) g/dl for darbepoetin alfa. The 95% CIs for both treatments were within the target hemoglobin range (11.0–13.0 g/dl), and the lower 95% confidence limit for the difference between groups (−0.50 g/dl) was above the predefined noninferiority margin (−0.75 g/dl), demonstrating noninferiority of vadadustat to darbepoetin alfa. Similar proportions of patients in each group reported AEs and serious AEs. The most frequent AEs with vadadustat were nasopharyngitis, diarrhea, and constipation. Conclusions In Japanese patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa, was effective up to week 52 in terms of average hemoglobin, and was generally well tolerated. These results suggest that vadadustat may be a potential treatment for anemia in this patient population.