Daily Vadadustat Equal to Darbepoetin Alfa for Anemia in Dialysis-Dependent CKD

Daily oral vadadustat was found non-inferior to darbepoetin alfa for the treatment of anemia in patients with dialysis-dependent chronic kidney disease (DD-CKD) converting from previous erythropoiesis-stimulating agents (ESAs), according to new Phase 3b trial data.¹

These data demonstrated a non-inferior change in mean hemoglobin from baseline to Weeks 20 to 26 with once-daily vadadustat, while the 3-times-weekly doses could not demonstrate non-inferiority. Both dose cohorts showed a lower risk of ESA rescue than darbepoetin alfa.

“Vadadustat offers a convenient oral alternative for the treatment of anemia in patients with DD-CKD, circumventing the limitations of parenteral or subcutaneous routes and providing an important option when iron supplementation and ESA treatment prove inadequate,” wrote the investigative team, led by Laura A. Kooienga, MD, Colorado Kidney Care.

Anemia prevalence is known to rise with CKD progression and has been linked with a lower quality of life, an increase in healthcare-related costs, and mortality.² Iron supplementation, ESAs, and red blood cell (RBC) transfusions comprise the treatment options available for anemia in CKD.

Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), was approved by the US Food and Drug Administration (FDA) for the treatment of DD-CKD in patients who had been receiving dialysis for ≥3 months.³

Based on data from the Phase 3 INNO2VATE trials, vadadustat showed non-inferiority to darbepoietin alfa for the primary safety outcome of time to first major adverse cardiovascular event (MACE) and the primary efficacy endpoint of correcting and maintaining hemoglobin levels.⁴

These patients were initiated with vadadustat 300 mg once daily, but some switching from ESAs experienced an initial decline in hemoglobin, which resolved with an increased dose. In the current trial, Kooienga and colleagues measured the mean change in hemoglobin from baseline with once-daily and 3-times-weekly dosing of vadadustat.¹

The Phase 3b, open-label, active-controlled trial randomized patients 1:1:1 to once-daily vadadustat (300 or 450 mg), 3-times-weekly vadadustat (600 or 750 mg), or darbepoetin alfa. The trial included the conversion (Weeks 0 to 20) and maintenance (Weeks 20 to 52) periods.

A total of 319 patients were randomized to vadadustat once-daily (n = 105), vadadustat 3-times-weekly (n = 104), or darbepoetin alfa (n = 108), with 2 patients not treated.

Upon analysis, the least-squares mean treatment difference between once-daily vadadustat and darbepoetin alfa from baseline to the primary evaluation period was –0.27 g/dL (95% CI, –0.55 to 0.01), with the lower bound above the prespecified noninferiority margin (–0.75 g/dL).

On the other hand, the least-squares mean treatment difference between vadadustat 3-times-weekly and darbepoetin alfa in the same period was –0.53 g/dL (95% CI, –0.80 to –0.25), missing the threshold of non-inferiority.

In the secondary evaluation period, the least-squares mean change from baseline between darbepoetin alfa and vadadustat was –0.40 (95% CI, –0.79 to –0.02) for the once-daily cohort and –0.42 (95% CI, –0.81 to –0.02) for the 3-times-weekly cohort.

Overall, the proportion of patients receiving ESA rescue, due to hemoglobin <9.5 g/dL, was higher in the darbepoetin alfa cohort compared with the vadadustat treatment cohorts. In the primary evaluation period, the proportion of patients who received any ESA rescue was 7.6%, 9.8%, and 15.6%, respectively.

Safety data revealed drug-related treatment-emergent adverse events (TEAEs) in 12.4% and 16.3% of patients in the vadadustat once-daily and 3-times-weekly groups, respectively, with none reported in the darbepoetin alfa cohort. TEAEs leading to study drug discontinuations were identified in 2.9%, 10.6%, and 2.8% in each cohort, respectively.

Overall, Kooienga and colleagues indicated the safety profiles between vadadustat and darbepoetin alfa, save for a higher incidence of gastrointestinal disorders with vadadustat treatment. The team noted the adverse event reporting may have been influenced by the open-label design of the trial.

“Results from this study support the safety and efficacy of vadadustat across a range of doses for managing anemia in patients with DD-CKD,” they added.

References

1. _{Kooienga L, Burke S, Kathresal A, et al. Safety and Efficacy of Vadadustat Once-Daily and 3-Times-Weekly in Dialysis-Dependent Chronic Kidney Disease Patients with Anemia. Kidney360. Published online September 4, 2024. doi:10.34067/KID.0000000567}
2. _{Hanna RM, Streja E, Kalantar-Zadeh K. Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin. Adv Ther. 2021;38(1):52-75. doi:10.1007/s12325-020-01524-6}
3. _{Abigail Brooks M. FDA approves Vadadustat (Vafseo) tablets for anemia due to CKD in adult patients on dialysis. HCP Live. March 28, 2024. Accessed September 5, 2024. https://www.hcplive.com/view/fda-approves-vadadustat-vafseo-anemia-ckd-adult-patients-dialysis.}
4. _{Eckardt KU, Agarwal R, Aswad A, et al. Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. N Engl J Med. 2021;384(17):1601-1612. doi:10.1056/NEJMoa2025956}