Once-Rejected Drug Now FDA Approved for CKD-Related Anemia

The FDA approved vadadustat (Vafseo) for chronic kidney disease (CKD)-related anemia in adults who have been on dialysis for at least 3 months, developer Akebia Therapeutics announced on Wednesday.

"Patients receiving maintenance dialysis would benefit from additional therapeutic options that can effectively increase and maintain hemoglobin concentrations within guideline-recommended target ranges," said co-chair of the drug's clinical development program Glenn Chertow, MD, MPH, of Stanford University in California, in a statement.

This was Akebia's second try at an approval. The FDA initially rejected the company's attempt at a broader indication for CKD-related anemia, stating that the data didn't support a favorable benefit-risk assessment of vadadustat for both dialysis and non-dialysis patients.

An estimated 500,000 U.S. adults on dialysis have CKD-related anemia, which has typically been treated with IV or injectable erythropoiesis-stimulating agents.

Vadadustat -- a once-daily, oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor -- works by activating the physiologic response to hypoxia to stimulate endogenous production of erythropoietin to manage anemia.

This is the second drug in this new class to gain approval for this indication. The first oral HIF-PH agent, daprodustat (Jesduvroq), was approved for adults with CKD-related anemia on dialysis by the FDA last year. Prior to that, HIF-PH inhibitor roxadustat had been rejected by the agency for CKD-related anemia in 2021 over concerns related to thrombotic risk.

Underpinning vadadustat's approval was data from the INNO₂VATE program. In this study, vadadustat was noninferior to darbepoetin alfa for efficacy in maintaining hemoglobin levels.

For patients with incident dialysis-dependent CKD, the mean differences in the change in hemoglobin concentrations for vadadustat compared with darbepoetin alfa were -0.31 g/dL (95% CI -0.53 to -0.10) at weeks 24 to 36 and -0.07 g/dL (95% CI -0.34 to 0.19) at weeks 40 to 52. For patients with prevalent dialysis-dependent CKD, the investigators saw average between-group differences in hemoglobin concentration change of -0.17 g/dL (95% CI -0.23 to -0.10) at weeks 24 to 36 and -0.18 g/dL (95% CI -0.25 to -0.12) at weeks 40 to 52.

In a sister study released simultaneously, the PRO₂TECT study of only non-dialysis-dependent CKD patients also met the pre-specified noninferiority endpoint for hematologic efficacy compared with darbepoetin alfa. But in this non-dialysis-dependent population, a cardiovascular safety signal emerged that was not seen in the dialysis-dependent group -- following the same pattern as daprodustat.

The most common adverse reactions that occurred in at least 10% of vadadustat-treated patients were hypertension and diarrhea.

The label will carry a boxed warning about an increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access. Other warnings on the label include the risk for hepatotoxicity, hypertension, seizures, gastrointestinal erosion, and malignancy.

The drug shouldn't be used in patients with uncontrolled hypertension or as a substitute for red blood cell transfusions in patients who require immediate correction of anemia.

Vadadustat's label also details specific instructions about potential drug interactions with iron supplements as well as iron- and non-iron-containing phosphate binders, statins, and breast cancer resistance protein (BCRP) substrates like 5-fluorouracil and a number of other cancer drugs.

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