Background Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. Methods The efficacy and safety of vadadustat, compared with darbepoetin alfa, was determined in a phase 3 double-blind study in Japanese anemic patients on hemodialysis. Patients receiving erythropoiesis-stimulating agents (ESAs) were randomized and switched to either vadadustat or darbepoetin alfa for 52 weeks. Doses were adjusted to maintain a hemoglobin level of 10.0–12.0 g/dL. The primary endpoint was average hemoglobin level at weeks 20 and 24. Results Of 323 randomized patients, 120 and 135 completed the 52-week treatment period in the vadadustat and darbepoetin alfa groups, respectively. The average hemoglobin levels at weeks 20 and 24 (least square mean [LSM] and 95% confidence interval [CI]) were 10.61 (10.45–10.76) and 10.65 (10.50–10.80) g/dL in the vadadustat and darbepoetin alfa groups, respectively, demonstrating vadadustat’s non-inferiority to darbepoetin alfa (difference, −0.05 g/dL; 95% CI, −0.26–0.17). In both groups, the mean hemoglobin levels were maintained within the target range for 52 weeks. Furthermore, irrespective of patient backgrounds, the LSMs at week 52 were within the target range. The most common adverse events were nasopharyngitis, diarrhea, and shunt stenosis, which occurred at similar frequencies in both groups. No new safety concerns were identified. Conclusions Vadadustat was as well tolerated and effective as darbepoetin alfa in maintaining hemoglobin levels within the target range. The findings suggest that vadadustat can be an alternative to ESA in the management of anemia in Japanese hemodialysis patients receiving ESA (Clinical Trials.gov, NCT03439137).

BackgroundStandard 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.MethodsIn 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.ResultsA 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.ConclusionsIn 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.

Purpose: Vadadustat is an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in chronic kidney disease. This study investigated drug-drug interactions between vadadustat and oral iron supplements or iron-containing phosphate binders commonly used in Japanese clinical practice by conducting in vitro mechanistic and clinical pharmacokinetic studies.Methods: In the in vitro assessment, chelate formation of vadadustat with iron-containing agents was investigated in water and in a fed-state simulated intestinal fluid. Chelate formation was assessed by observation of a chelate-specific color, and the concentration of vadadustat was determined. In the single-dose, open-label, randomized, crossover clinical study, healthy male participants received 150 mg of vadadustat with or without oral iron-containing agents. Pharmacokinetic data were collected for up to 24 hours after vadadustat administration. Participants were monitored for adverse events during the study.Findings: Vadadustat formed a chelate precipitate with ferrous sulfate and ferric nitrate, as shown by development of a specific bright orange color in water. The proportions of vadadustat dissolved in the supernatant were 2% and 18%, respectively. Vadadustat did not form a chelate precipitate in a fed-state simulated intestinal fluid in the presence of sodium ferrous citrate, ferric citrate hydrate, or sucroferric oxyhydroxide; the proportion of vadadustat in supernatant ranged from 63% to 89%. In the clinical pharmacokinetic study, coadministration of vadadustat with sodium ferrous citrate, ferric citrate hydrate, sucroferric oxyhydroxide, or ferrous sulfate decreased the AUC 0-∞ by 54.0% to 89.7% and C max by 42.1% to 91.9%. No serious adverse events were reported.Implications: Chelate formation of vadadustat with iron-containing agents was confirmed by in vitro analysis and depended on the type of ironcontaining agent. The AUC 0-∞ and C max of vadadustat decreased when coadministered with oral ironcontaining agents. Our data suggest that the decreases in AUC 0-∞ and C max are a result of chelation in the gastrointestinal tract; therefore, coadministration of iron-containing agents with vadadustat should use a dosing interval. ClinicalTrials.gov Identifier: NCT03645863.

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