Akebia Ends VOICE Trial Early as Vafseo Shows Superior Safety Over ESAs

Akebia Therapeutics and U.S. Renal Care (USRC) have stopped the Phase 4 Vafseo Outcomes In-Center Experience (VOICE) trial (NCT06520826) early after a planned interim analysis demonstrated a statistically significant improvement in the primary composite safety endpoint for Vafseo® (vadadustat) administered three times weekly during hemodialysis. The Independent Data Monitoring Committee and Trial Steering Committee recommended terminating the study after predefined stopping criteria were met.

The interim findings showed that Vafseo outperformed standard erythropoiesis-stimulating agents (ESAs) in reducing the hierarchical composite endpoint of all-cause mortality and hospitalization, with the benefit primarily driven by fewer hospitalizations. The results reinforce earlier observations from the Phase 3 INNO2VATE program and suggest that intermittent in-center dosing may deliver meaningful clinical benefits in routine dialysis practice.

Clinical Background

Vafseo is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved by the U.S. FDA in March 2024 for treating anemia due to chronic kidney disease (CKD) in adults receiving dialysis for at least three months. The drug became commercially available in the United States in January 2025 and is currently approved as a once-daily oral therapy.

Anemia is a common complication of advanced CKD, resulting from inadequate erythropoietin production by the kidneys. Standard treatment relies on injectable ESAs, which require regular administration and monitoring. HIF-PHIs stimulate endogenous erythropoietin production while improving iron metabolism, offering an oral alternative for anemia management.

VOICE Trial Results

The investigator-initiated, multicenter, randomized, open-label, active-controlled non-inferiority trial enrolled 2,116 patients receiving in-center hemodialysis with end-stage kidney disease and CKD-related anemia. Unlike the approved once-daily regimen, the study evaluated vadadustat administered three times weekly (TIW) during dialysis sessions.

At the prespecified interim analysis using a June 1, 2026 data cutoff, the trial met its stopping criteria with a win odds ratio of 1.16 (95% CI, 1.06–1.28; p=0.0016), establishing both non-inferiority and superiority for the primary composite endpoint.

Patients treated with Vafseo experienced 1.11 hospitalizations per patient-year, compared with 1.23 hospitalizations per patient-year in the ESA group, corresponding to an incidence rate ratio of 0.90 (95% CI, 0.824–0.988). Mortality rates were nearly identical between treatment groups, with 8.77% versus 8.78% per 100 patient-years (incidence rate ratio 1.00; 95% CI, 0.718–1.391), indicating that the overall benefit resulted from fewer hospital admissions rather than differences in survival.

Findings Reinforce Earlier Evidence

Primary investigator Dr. Geoffrey A. Block said the interim analysis confirmed a clinically meaningful reduction in the composite endpoint, largely attributable to fewer hospitalizations. He added that the investigators intend to present the complete VOICE dataset at an upcoming scientific meeting.

Executive Steering Committee member Dr. Glenn M. Chertow noted that the outcomes closely mirrored a recently published post hoc win odds analysis from the Phase 3 INNO2VATE program, despite differences in dosing schedules. The consistency across studies strengthens evidence that vadadustat may reduce the combined risk of death or hospitalization compared with conventional ESA therapy in dialysis patients.

Regulatory Path Forward

Akebia and USRC plan to submit the full VOICE trial results for presentation at a forthcoming scientific congress. Although Vafseo remains approved in the United States as a once-daily oral therapy, the VOICE findings provide new evidence supporting a three-times-weekly in-center dosing strategy and may influence future clinical practice and research evaluating anemia management in patients receiving maintenance hemodialysis.

Reference

U.S. Renal Care and Akebia Announce Interim Analysis of VOICE Trial Demonstrated Overwhelming Statistical Evidence of Improved Safety Outcomes for Patients Treated with Vafseo versus an ESA | Akebia Therapeutics