The US Food and Drug Administration approved the first oral treatment for anemia on February 1, specifying that daprodustat (Jesduvroq) was labeled for anemia caused by chronic kidney disease (CKD) in adults who have been on dialysis for at least 4 months.
In announcing this, the FDA’s statement highlighted that daprodustat is not approved for use by patients not on dialysis even if they have advanced-stage CKD, a condition notorious for often triggering significant anemia that requires treatment. The only existing treatment options for these patients are injected stimulants of red blood cell production (erythropoiesis-stimulating agents [ESAs]) or blood transfusions.
“With an oral drug option in addition to the FDA-approved injection options, adults with chronic kidney disease on dialysis now have multiple ways to treat their anemia,” said the FDA’s Ann Farrell, MD, in the agency’s announcement.
“This approval demonstrates the FDA’s commitment to helping bring a range of therapeutic options to patients with chronic diseases. Patients can consult with their healthcare providers to select the option that is most appropriate,” added Farrell, director of the Division of Non-Malignant Hematology in the FDA’s Center for Drug Evaluation and Research in Silver Spring, Maryland.
The agency’s approval of daprodustat for patients on dialysis but not for patients with CKD and anemia who are not on dialysis was consistent with the recommendations it received from the advisory committee that considered daprodustat in a meeting on October 26, 2022. At that session, the advisory committee voted 13-3 that the benefits of daprodustat outweigh its risks for treating anemia in adults with CKD and on dialysis, but it also voted 11-5 against the proposition that daprodustat’s benefits outweighed its risks in patients with CKD who do not require dialysis.
The Focus Is Safety
The advisory committee’s split vote on daprodustat focused on safety concerns raised by results of the two large, pivotal trials for the agent, ASCEND-D (in patients on dialysis) and ASCEND-ND (in patients not on dialysis), both published in late 2021 in The New England Journal of Medicine. Both trials compared the safety and efficacy of oral daprodustat with injected treatment with an ESA, the currently preferred approach to treating anemia in all patients with CKD.
FDA staffers who spoke during the advisory committee meeting acknowledged that daprodustat’s effectiveness, as documented in both trials, was not the issue. The agency agreed that “substantial evidence of effectiveness is established,” said Justin Penzenstadler, PharmD, a clinical reviewer in the FDA Office of Cardiology, Hematology, and Nephrology.
Penzenstadler also cited the potential convenience of an oral agent for treating anemia compared with infusing or injecting an ESA, which requires patients to travel to receive treatment.
Intense scrutiny of daprodustat’s safety by both the advisory committee and the FDA’s staff stemmed in part from the history of two other agents from the same class as daprodustat — roxadustat and vadadustat — that both failed to receive approval because of safety concerns.
A Boxed Warning
Safety qualifications highlight daprodustat’s new label, which the FDA said will include a boxed warning stating that treatment with the agent risks causing blood clots that can trigger thrombotic vascular events including death; myocardial infarction; stroke; and blood clots in the lungs, legs, or dialysis access site. Other warnings and precautions include risks for hospitalization for heart failure, worsening hypertension, stomach erosions, and gastrointestinal bleeding.
The FDA’s approval statement also listed the most common adverse effects of daprodustat as hypertension, thrombotic vascular events, abdominal pain, dizziness, and allergic reactions. In addition, the agency advised that patients should not use daprodustat if they also take certain drugs that cause increased serum levels of the drug or if they have uncontrolled high blood pressure.
A statement released by GSK, the company that has developed and will market daprodustat, added these additional safety warnings and qualifications: “No trial has identified a hemoglobin target level, dose of Jesduvroq, or dosing strategy that does not increase” the risk for death and arterial venous thrombotic events. “Use the lowest dose of Jesduvroq sufficient to reduce the need for red blood cell transfusions. Jesduvroq has not been shown to improve quality of life, fatigue, or patient well-being. Jesduvroq is not indicated for use as a substitute for red blood cell transfusions in patients who require immediate correction of anemia.”
The drug class that daprodustat, roxadustat, and vadadustat all belong to is the hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, which stabilize HIF and thereby increase the secretion of endogenous erythropoietin and the production of red cells. This approach to resolving anemia mimics the physiologic effects that occur in people when they are at high altitudes.
According to the GSK statement, CKD affects approximately 39 million people in the United States and about 6 million of these people also have anemia. Approximately 810,000 of these people with CKD have end-stage renal disease, including about 558,000 patients on treatment with dialysis.
The ASCEND-D and ASCEND-ND trials were sponsored by GSK. Farrell and Penzenstadler had no disclosures.
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. Twitter: @mitchelzoler
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