The hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) class of agents for treating anemia in patients with chronic kidney disease (CKD) struck out with the US Food and Drug Administration (FDA) for a second time within the past 8 months.
The FDA declined to grant marketing approval for vadadustat on March 29, making it the second agent from the HIF-PHI class to get turned down. In August 2021, the FDA rejected the new drug application (NDA) for roxadustat, the first drug from the class to undergo FDA review.
In both cases the agency cited unresolved concerns about safety as its rationale for denying the applications.
According to a statement released on March 30 by Akebia Therapeutics, the company developing vadadustat, the FDA's complete response letter (CRL) said that "the data in the NDA do not support a favorable benefit–risk assessment of vadadustat for dialysis and nondialysis patients. The FDA expressed safety concerns noting failure to meet non-inferiority in MACE (major adverse cardiovascular events) in the nondialysis patient population, the increased risk of thromboembolic events, driven by vascular access thrombosis in dialysis patients, and the risk of drug-induced liver injury." The company also noted that the CRL "stated that Akebia could explore ways to potentially demonstrate a favorable benefit–risk assessment through new clinical trials."
Pivotal Trial Data From More Than 5600 Patients
Results from four pivotal trials that supplied the core data to support the NDA for vadadustat came out about a year ago in two PRO2TECT trials, which together randomized 1751 patients with CKD who did not yet require dialysis, and in the two INO2VATE trials, which together randomized 3923 patients with CKD who were on dialysis.
The FDA did not convene an advisory committee to review the NDA for vadadustat before making its decision, but the agency had an advisory committee vet roxadustat before the agency released its judgment in August 2021. The roxadustat advisory committee voted 1-13 and 2-12 against recommending approval for roxadustat for patients with CKD not on or on dialysis, respectively, as reported by Medscape Medical News, a decision also driven largely by safety considerations. Roxadustat (Evrenzo, Astellas) received marketing approval from the European Union in August 2021.
Pivotal trial results for a third agent from the same class, daprodustat, came out in late 2021, with findings from 3872 randomized patients with CKD who were not on dialysis in ASCEND-ND, and from 2964 randomized patients with CKD who were on dialysis in ASCEND-D. GlaxoSmithKline, the company developing daprodustat, has not yet announced acceptance by the FDA of an NDA for the agent, but in March 2022 the company announced that the European Medicines Agency had validated a marketing application for the drug.
When the results for daprodustat from ASCEND-D and ASCEND-ND came out in 2021, Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the studies, commented that the safety findings for daprodustat were "looking really good," a judgment that could presage a different regulatory outcome for the agent compared with the fate of the first two agents from the HIF-PHI class.
The drug class takes advantage of a normal regulatory pathway that boosts hemoglobin production in response to hypoxia by increasing endogenous erythropoietin, improving iron availability, and reducing hepcidin. Five agents in the HIF-PHI class are already on the market in Japan or China, including roxadustat.
Wish has reported being a consultant for GlaxoSmithKline, an adviser for AstraZeneca, Akebia, Otsuka, Rockwell Medical, and Vifor, and being a speaker on behalf of AstraZeneca and Akebia.
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler
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Cite this: FDA Turns Down Vadadustat for CKD Anemia - Medscape - Mar 31, 2022.