FDA Approves Vadadustat (Vafseo) Tablets for Anemia Due to CKD in Adult Patients on Dialysis

Credit: US Food and Drug Administration

The US Food and Drug Administration (FDA) has approved vadadustat (Vafseo) for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis.¹

Announced by Akebia Therapeutics on March 27, 2024, the approval is based on is based on efficacy and safety data from the INNO₂VATE program and an assessment of post-marketing safety data from Japan where vadadustat was launched in August 2020. The decision comes nearly 2 years after the oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor was issued a Complete Response Letter (CRL) due to a lack of favorable risk-benefit assessment in dialysis and non-dialysis patients, with concern over the agent’s failure to meet noninferiority in major adverse cardiovascular events among non-dialysis patients in phase 3 trials.^1,2

According to the release, the approval includes a Boxed Warning regarding increased risk of death, myocardial infarction, stroke, venous thromboembolism and thrombosis of vascular access.¹

"With the approval of Vafseo in the US, we're proud to deliver an alternative treatment option for the hundreds of thousands of Americans on dialysis who are diagnosed with anemia due to CKD," said John P. Butler, chief executive officer of Akebia, in a press release.¹

An oral HIF-PH inhibitor, vadadustat is designed to mimic the physiologic effect of altitude on oxygen availability and subsequently stabilize hypoxia-inducible factor, leading to increased red blood cell production and improved oxygen delivery to tissues.¹

Akebia Therapeutics filed its initial New Drug Application (NDA) for vadadustat on June 1, 2022, supported by data from a phase 3 program composed of 4 trials assessing its use in patients with dialysis-dependent and non-dialysis-dependent CKD. Vadadustat was assigned a Prescription Drug User Fee Act (PDUFA) date of March 29, 2022, but the HIF-PH inhibitor was issued a CRL a day after this target action date on March 30, 2022.²

Despite positive phase 3 data showing vadadustat’s noninferiority to erythropoiesis-stimulating agent darbepoetin alfa in hemoglobin concentration changes at weeks 24-36, vadadustat was also associated with a 17% increased risk of major adverse cardiovascular events compared to darbepoetin alfa (Hazard ratio [HR], 1.17; 95% CI, 1.01 – 1.36). Accordingly, in the CRL, the FDA cited an unfavorable risk-benefit assessment in dialysis and non-dialysis patients and concern over the agent’s failure to meet noninferiority in major adverse cardiovascular events among non-dialysis patients. The FDA additionally expressed specific concerns over the risk of drug-induced liver injury and the increased risk of thromboembolic events, which was driven by vascular access thrombosis in dialysis patients.³

Upon receipt of the CRL, Akebia Therapeutics submitted a Formal Dispute Resolution Request and eventually resubmitted their NDA for vadadustat, addressing the issues raised in the CRL and including post-marketing safety data from > 10,000 patients in Japan where vadadustat had been approved for more than 3 years. At the time of acceptance, the FDA classified the resubmission as a class 2 response, resulting in a 6-month review period from the date of resubmission.^3,4

"We are tremendously grateful for the patients, physicians, investigators, and site coordinators who participated in our clinical trials that led to this important approval. This milestone is the culmination of years of perseverance by Akebia employees and partners committed to bettering the lives of people impacted by kidney disease," Butler concluded.¹

References:

1. ^{Akebia Therapeutics. Akebia Receives FDA Approval of Vafseo® (vadadustat) Tablets for the Treatment of Anemia due to Chronic Kidney Disease in Adult Patients on Dialysis. March 27, 2024. Accessed March 27, 2024. https://ir.akebia.com/news-releases/news-release-details/akebia-receives-fda-approval-vafseor-vadadustat-tablets}
2. ^{FDA Issues CRL for Vadadustat in Treatment of Anemia Due to CKD. HCPLive. March 30, 2022. Accessed March 27, 2024. https://www.hcplive.com/view/fda-issues-crl-for-vadadustat-in-anemia-due-to-ckd}
3. ^{Kunzmann K. Akebia Continues FDA Appeal for Vadadustat as CKD Anemia Treatment. HCPLive. February 21, 2023. Accessed March 27, 2024. https://www.hcplive.com/view/akebia-continues-fda-appeal-vadadustat-ckd-anemia-treatment}
4. ^{Campbell P. Akebia Announces FDA Acceptance of Vadadustat Resubmission for Anemia. HCPLive. October 25, 2023. Accessed March 27, 2024. https://www.hcplive.com/view/akebia-announces-fda-acceptance-on-vadadustat-resubmission}