Oral Vadadustat Non-Inferior to Darbepoetin Alfa for Managing Anemia in dialysis-dependent CKD Patients: Study

Anemia incidence increases as CKD progresses, and hence there is a continuous demand for effective treatments. Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor and has been approved by the US FDA for the treatment of anemia in dialysis-dependent chronic kidney disease patients for more than three months. In prior Phase 3 INNO2VATE trials, vadadustat was reported to be non-inferior compared to darbepoetin alfa in maintaining hemoglobin levels and in reducing the time to first major adverse cardiovascular event.

The Phase 3b study led by Dr. Laura A. Kooienga of Colorado Kidney Care was an open-label, active-controlled trial including 319 DD-CKD patients. Patients were randomized 1:1:1 to once-daily vadadustat (300 or 450 mg), 3-times-weekly vadadustat (600 or 750 mg), or darbepoetin alfa. The study comprised two periods: a conversion period (Weeks 0 to 20) and a maintenance period (Weeks 20 to 52). The primary objective of the study was to determine the average change in hemoglobin from baseline over the period of conversion, focusing on non-inferiority to darbepoetin alfa.

• The trial showed that vadadustat QD was non-inferior to darbepoetin alfa, in a least-squares mean treatment difference of –0.27 g/dL [95% CI, –0.55 to 0.01].

• Vadadustat dosing 3 times a week did not meet the non-inferiority margin, with a least-squares mean treatment difference of –0.53 g/dL [95% CI, –0.80 to –0.25].

• The least-squares mean change from baseline for once-daily vadadustat for secondary endpoints was –0.40 (95% CI, –0.79 to –0.02) versus darbepoetin alfa and –0.42 (95% CI, –0.81 to –0.02) in the 3-times-weekly dosing.

• A lower percentage of patients treated with vadadustat required ESA rescue for a hemoglobin level less than 9.5 g/dL (7.6% and 9.8% in the once-daily and 3-times-weekly groups, respectively, compared with 15.6% for darbepoetin alfa).

• Safety Profile Regarding safety, TEAEs were reported for 12.4% of patients in the once-daily vadadustat group and for 16.3% in the 3-times-weekly group, while for patients in the darbepoetin alfa cohort, no such profile was reported.

• TEAEs leading to discontinuation occurred for 2.9% in the once-daily vadadustat group, 10.6% in the 3-times-a-week group, and 2.8% in the darbepoetin alfa group.

• Gastrointestinal disorders were more frequent in patients receiving vadadustat. Overall, the investigators pointed out that the open-label design might have impacted the reporting of adverse events.

Vadadustat is a safe and effective oral treatment for the management of anemia in DD-CKD patients; once-daily dosing has proved non-inferior to darbepoetin alfa. The current study supports the use of vadadustat, although additional studies will be needed for the continued evaluation of dosing regimens and long-term safety.

Reference:

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