Vadadustat Shows Promise in Anemia Treatment for CKD

Laura Kooienga, MD

Credit: Colorado Kidney Care

A phase 3b study comparing vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, with darbepoetin alfa (DA) for treating anemia in dialysis-dependent chronic kidney disease (CKD), showed vadadustat once-daily offers a viable alternative to DA for managing anemia in CKD. However, the 3-times-weekly regimen did not show significant equivalent efficacy.

Anemia is common among patients with CKD and mainly results from low erythropoietin (EPO) production due to reductions in kidney function. As CKD progresses, the prevalence of anemia increases and is linked to worse health-related quality of life coupled with increased cardiovascular events, healthcare costs and mortality.

The open-label, active-controlled sponsor blinded trial randomized patients 1:1:1 to receive vadadustat once-daily, vadadustat 3-times-weekly or DA. Eligible patients were aged ≥ 18 years and were receiving chronic outpatient in-center hemodialysis 3-times-weekly for end-stage renal disease for at least 12 weeks before screening. They were also required to be treated with an approved erythropoiesis stimulating agent (ESA) for at least 8 weeks prior to screening and have had 2 hemoglobin values at least 4 days apart within the 8 – 11 g/dL range in the United States and 9 – 12 g/dL range in Europe. Patients were excluded from the study if their anemia was shown to be caused by factors unrelated to CKD or if they had uncontrolled hypertension or recent cardiovascular events.

Vadadustat was given orally in dosages ranging from 150 mg and 450 mg. For patients with low ESA, the starting dose was either 300 mg once a day or 600 mg 3 times a week. The high ESA-dose cohort received 540 mg once a day or 750 mg 3 times a week. The primary endpoint was the mean change in hemoglobin concentration from baseline to weeks 20 – 26, while the secondary efficacy endpoint was changes from baseline to weeks 46 – 52.

The safety population included 317 patients, of which 105 received once daily vadadustat, 104 received 3-times-weekly vadadustat and 108 were treated with DA. The demographics and baseline characteristics were comparable between treatment groups.

Hemoglobin levels were consistent in the once-daily group compared with baseline and were higher than baseline compared with the DA group. Levels were lower than baseline in the 3-times-weekly cohort. Both vadadustat groups demonstrated noninferiority to DA regarding changes in hemoglobin concentrations from baseline in the per protocol population; however, in the randomized population, only the once-daily group showed noninferiority.

“Although vadadustat administered 3-times-weekly did not meet the criteria for noninferiority, this dosing regimen proved comparable to vadadustat once-daily for changes in mean hemoglobin levels,” wrote a team of investigators led by Laura Kooienga, MD, associated with Colorado Kidney Care in Aurora, Colorado.

Data also showed a higher need for ESA rescue in the DA group, though safety profiles were comparable across all treatments. Treatment-emergent adverse events were reported in 12.4% of patients in the once-daily cohort and 16.3% in the 3-times-weekly cohort. They most commonly included diarrhea, nausea, vomiting and abdominal pain. However, no drug-related adverse events were observed in the DA group.

“Vadadustat offers a convenient oral alternative for the treatment of anemia in patients with dialysis-dependent chronic kidney disease (DD-CKD), circumventing the limitations of parenteral or subcutaneous routes and providing an important option when iron supplementation and ESA treatment prove inadequate,” investigators concluded. “Results from this study support the safety and efficacy of vadadustat across a range of doses for managing anemia in patients with DD-CKD.”