FDA Says No to Vadadustat Approval Due to Safety Concerns

anemia, red blood cells
Hemotransfusion in treatment of anemia, 3D illustration showing two populations of red blood cells, small hypochromic red blood cells and normal. A small lymphocyte is drawn for size comparison
The NDA submission included data from 36 clinical trials involving over 8000 patients.

The Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) to Akebia Therapeutics regarding the New Drug Application (NDA) for vadadustat, an investigational therapy for anemia due to chronic kidney disease (CKD).

Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor designed to mimic the physiologic effect of altitude on oxygen availability. This results in increased red blood cell production and improved oxygen delivery to tissues.

The NDA submission included data from 36 clinical trials involving over 8000 patients. Findings from the INNO2VATE program, which included 2 open-label, active-controlled phase 3 trials, showed that vadadustat was noninferior to darbepoetin alfa in adult patients on dialysis with anemia due to CKD. Similar efficacy results were observed in the phase 3 PRO2TECT randomized trials in patients with anemia due to non-dialysis dependent CKD.

However, safety findings from the PRO2TECT trials contrasted with those in the INNO2VATE trials with regard to major adverse cardiovascular events (MACE; defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke). Both INNO2VATE studies met the primary safety endpoint of noninferiority for MACE, while the combined data from PRO2TECT showed a 17% increased risk of MACE with vadadustat.

In the CRL, the FDA stated that the data do not support a favorable benefit-risk assessment for vadadustat for dialysis and non-dialysis patients. “Failure to meet noninferiority in MACE in the non-dialysis patient population, the increased risk of thromboembolic events, driven by vascular access thrombosis in dialysis patients, and the risk of drug-induced liver injury” were all safety concerns noted in the letter. The FDA recommended that the Company conduct new clinical trials to address these issues.

“We are extremely disappointed to receive a CRL for vadadustat, a therapy that has the potential to help patients with anemia due to CKD,” said John P. Butler, CEO of Akebia. “We continue to believe the data are supportive of a positive benefit-risk assessment of vadadustat for patients with anemia due to CKD, particularly in dialysis patients.”


Akebia Therapeutics receives Complete Response Letter from the FDA for vadadustat for the treatment of anemia due to chronic kidney disease in adult patients. News release. Akebia Therapeutics. March 30, 2022. Accessed March 31, 2022. https://www.prnewswire.com/news-releases/akebia-therapeutics-receives-complete-response-letter-from-the-fda-for-vadadustat-for-the-treatment-of-anemia-due-to-chronic-kidney-disease-in-adult-patients-301514075.html