Vadadustat and Darbepoetin Alfa Show Similar Safety, Efficacy in Patients With NDD-CKD and DD-CKD

Prespecified analyses published in the Journal of the American Society of Nephrology demonstrated that the safety and efficacy of vadadustat (Vafseo; Akebia Therapeutics) and darbepoetin alfa (Aranesp; Amgen) in patients with dialysis-dependent chronic kidney disease (DD-CKD) both inside and outside the US were similar. Additionally, the efficacy and safety of these treatments were also similar in US patients with nondialysis-dependent CKD (NDD-CKD); however, the risk for major adverse cardiovascular events (MACEs) was higher with vadadustat than with darbepoetin alfa outside of the US.^1,2

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Vadadustat was approved by the FDA in March 2024 for the treatment of CKD-related anemia in adults who have been receiving dialysis for at least 3 months. It is a once-daily oral hypoxia-inducible factor prolyl hydroxylase inhibitor that activates the physiologic response to hypoxia to stimulate endogenous production of erythropoietin, therefore increasing hemoglobin and red blood cell production to manage anemia in patients with CKD. According to an Akebia Therapeutics news release, the treatment has been available in the US since January 2025.²

The treatment’s global clinical program is comprised of 4 open-label, randomized, noninferiority phase 3 trials that compared vadadustat and darbepoetin alfa in patients with CKD-related anemia. Two of these trials, INNO2VATE-CORRECTION (NCT02865850) and INNO2VATE-CONVERSION (NCT02892149), enrolled patients with DD-CKD, and the others, PRO2TECT-CORRECTION (NCT02648347) and PRO2TECT-CONVERSION (NCT02680574), enrolled those with NDD-CKD. Although vadadustat previously met prespecified noninferiority criteria for hematologic efficacy globally, it did not meet noninferiority criteria for cardiovascular safety in NDD-CKD populations. These trials, according to the investigators, considered regional differences in treatment practices, including hemoglobin targets within (10–11 g/dl) and outside the US (10–12 g/dl).¹

To examine region-specific outcomes, the investigators performed prespecified analyses for US and non-US patient subgroups from the vadadustat global program. The primary safety end point was the first occurrence of MACE, which was defined as death from any cause, nonfatal myocardial infarction, or stroke. The primary efficacy end point was change in hemoglobin from baseline to average values during weeks 24 through 36.¹

Approximately 55% (n = 4084) of the total 7399 randomly assigned patients were enrolled in the US. In pooled analyses of all US patients, MACE risk was observed to be similar among vadadustat-treated and darbepoetin alfa-treated patients (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.90–1.17). HRs were also similar for US patients with DD-CKD (HR, 1.00; 95% CI, 0.84–1.18) and NDD-CKD (HR, 1.06; 95% CI, 0.87–1.29).¹

Further, in pooled analyses of non-US patients, MACE risk was observed to be numerically higher among vadadustat-treated patients (HR, 1.12; 95% CI, 0.94–1.33), with the higher risk primarily attributed to the NDD-CKD subgroup (HR, 1.29; 95% CI, 1.03–1.60). MACE risk was similar among vadadustat-treated and darbepoetin alfa–treated patients (HR, 0.88; 95% CI, 0.67 to 1.17) in the non-US DD-CKD subgroup. Changes in hemoglobin were similar among treatment groups in all regions, as were rates of treatment-emergent and serious adverse events, wrote the authors.¹

“Geographic-specific prespecified analyses of the vadadustat global phase 3 clinical program are important data as physicians in the US are making care decisions for patients with CKD-related anemia,” Steven K. Burke, MD, chief medical officer and senior vice president of research and development at Akebia Therapeutics, said in the news release. “The analyses reflect how regional differences in clinical trial patient baseline characteristics, hemoglobin targets, and access to health care services and other regional clinical practices can ultimately contribute to differing outcomes in a global trial.”²

REFERENCES

1. Chertow GM, Eckardt KU, Sarnak MJ, et al. Safety and Efficacy of Vadadustat for the Treatment of CKD-Related Anemia within and outside the United States. JASN. Published online 2025, May 13. doi:10.1681/ASN.0000000708

2. Akebia Therapeutics. Vadadustat U.S. Patient Data from Global Phase 3 Clinical Program Published in Journal of the American Society of Nephrology. News release. June 4, 2025. Accessed June 5, 2025. https://ir.akebia.com/news-releases/news-release-details/vadadustat-us-patient-data-global-phase-3-clinical-program