The company announced more feedback from the FDA after receiving a Complete Response Letter last March.
Drug candidate vadadustat’s pathway to US Food and Drug Administration (FDA) approval continues to encounter hurdles.
Biopharmaceutical company Akebia Therapeutics announced today that their Formal Dispute Resolution Request regarding an FDA Complete Response Letter (CRL) for vadadustat’s application last year is now being reviewed by Peter Stein, MD, director of the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research (CDER).1
Stein notified Akebia of the agency’s need to internally consult with CDER experts in nephrology, cardiology and liver safety regarding the company’s post-CRL appeal. Akebia now anticipates to be notified of a response from Stein and his office within 30 days of said internal discussions.
Akebia originally submitted a New Drug Application (NDA) for vadadustat as a treatment of anemia due to chronic kidney disease (CKD) in adult patients either with or without dialysis to the FDA in June 2021.2 An oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, vadadustat was supported by data from a pair of phase 3 trials showing noninferiority to erythropoiesis-stimulating agent (ESA) darbepoetin alfa in hemoglobin concentration changes at weeks 24 – 36.3
However, vadadustat was also associated with a 17% increased risk of major adverse cardiovascular events (MACE) compared to darbepoetin alfa (hazard ratio [HR], 1.17; 95% CI, 1.01 – 1.36). “Analysis of events in the current trials revealed that the higher risk that was observed among patients who had been randomly assigned to the vadadustat group than among those in the darbepoetin alfa group was due largely to an excess of nonfatal myocardial infarctions and a higher incidence of death from noncardiovascular causes,” investigators wrote. “We could not identify a reason for the excess in noncardiovascular deaths.”
The company received a CRL from the FDA in March 2022; the FDA stated their NDA-supporting data did not support a favorable benefit-risk profile for the indicated population based on the failure to meet non-inferiority in MACE safety outcomes in their phase 3 trials.4
“We are extremely disappointed to receive a CRL for vadadustat, a therapy that has the potential to help patients with anemia due to CKD,” John P. Butler, Chief Executive Officer of Akebia, said in a statement at the time. “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.”
During the CRL appeal process, drug class rival daprodustate (Jesduvroq), from GlaxoSmithKline, was approved by the FDA to treat anemia in patients with CKD who are on dialysis earlier this month—making the first HIF-PH approved for this patient population.5