Vadadustat Three Times Weekly in Patients With Anemia Due to Dialysis-Dependent CKD.

RATIONALE & OBJECTIVE: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) may offer an alternative to erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in the setting of chronic kidney disease (CKD). The objective of this study was to investigate the efficacy and safety of conversion from the long-acting ESA methoxy polyethylene glycol-epoetin-ß (MPG-EPO) to the oral HIF-PHI vadadustat 3 times weekly versus maintenance therapy with MPG-EPO.

STUDY DESIGN

Phase 3b, open-label, noninferiority trial.

SETTING & PARTICIPANTS: Multicenter study in the United States in 456 adult participants with anemia and dialysis-dependent CKD.

INTERVENTION

Participants were randomized 1:1:1 to vadadustat at a starting dose of 600mg thrice weekly, vadadustat at a starting dose of 900mg thrice weekly, or MPG-EPO for up to 52 treatment weeks and 4 safety follow-up weeks after the end of treatment or early termination.

OUTCOMES

Primary and secondary efficacy end points were the mean change in hemoglobin concentration from baseline during primary (weeks 20-26) and secondary (weeks 46-52) evaluation periods, respectively. Noninferiority was specified as a lower bound of the 95% CI above -0.75g/dL for the difference in mean change in hemoglobin concentration from baseline. Other efficacy end points were the proportion of participants with hemoglobin levels within the target range and the proportions of participants requiring ESA or red blood cell transfusion rescue for anemia during the evaluation periods. Primary safety end points were any treatment-emergent and serious adverse events (AEs).

RESULTS

After combining the vadadustat groups (600mg and 900mg thrice weekly; n=304), vadadustat was noninferior to MPG-EPO (n=152) for primary (least-squares mean treatment difference, -0.33; 95% CI, -0.53 to-0.13) and secondary (-0.33; -0.56 to-0.09) efficacy end points. Mean hemoglobin concentrations were stable for all groups except for an initial slight decrease in the vadadustat 600mg group, which stabilized by week 12. ESA rescue for anemia was more frequent in the MPG-EPO group (primary evaluation period, 27.7%; secondary evaluation period, 16.2%) than in the combined vadadustat (14.2%; 7.3%) groups. Transfusion rates were low and occurred at similar rates across treatment groups (2.7% and 4.0% in the combined vadadustat and MPG-EPO groups, respectively). The incidences of any treatment-emergent and serious treatment-emergent AEs were similar across treatment groups.

LIMITATIONS

Potential errors in attribution of AEs as drug-related.

CONCLUSIONS

Three-times-weekly vadadustat was noninferior to MPG-EPO in its effect on hemoglobin levels without detectable differences in AEs.

FUNDING

Funding from a private entity (Akebia Therapeutics, Inc).

TRIAL REGISTRATION

Registered at ClinicalTrials.gov with study identifier NCT04707768.

PLAIN-LANGUAGE SUMMARY: Vadadustat, taken 3 times a week, was noninferior to methoxy polyethylene glycol-epoetin-ß (MPG-EPO) in treating anemia. Vadadustat is an oral drug used to treat anemia in people with chronic kidney disease. This study enrolled participants undergoing dialysis for kidney failure and compared the efficacy and safety of continuing to receive MPG-EPO, a long-acting injectable anemia treatment, or switching to vadadustat, taken by mouth 3 times per week for 1 year. Vadadustat was noninferior to MPG-EPO in maintaining hemoglobin levels. Hemoglobin levels remained stable across all groups, except for a slight decrease in the lower-dose vadadustat group, which stabilized with dose titration by week 12. The occurrence of new or serious side effects was similar across treatment groups.