FDA Approves Oral Agent for Anemia in Dialysis: Daprodustat Is First HIF-PHI to Hit Market

The US Food and Drug Administration (FDA) announced in February its approval of the first oral agent to treat anemia in patients on dialysis.

Daprodustat is the first in the class of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) to receive approval after the FDA declined to approve two previous drugs in the class—roxadustat and vadadustat—over safety concerns.

In its announcement, the agency specified that daprodustat received approval for use in patients who have been on dialysis for at least 4 months but not “for patients with anemia due to chronic kidney disease who are not on dialysis because its safety has not been established in that population.” The FDA's action conformed to the recommendations of the advisory committee that considered daprodustat's efficacy and safety data in the fall of 2022. “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,” Ann Farrell, MD, director of the FDA's Division of Non-Malignant Hematology, said in a press release (1).

Injections of erythropoietin-stimulating agents (ESAs) have been a mainstay in treatment of the anemia common in patients with chronic kidney disease for some 30 years and greatly reduced the need for blood transfusions. However, the kidney care community has been looking forward to an alternative agent because ESAs are associated with cardiovascular risks, and up to 10% of patients do not respond adequately to ESAs.

[T]he kidney care community has been looking forward to an alternative agent because ESAs are associated with cardiovascular risks.

Daprodustat's initial use will most likely be to treat these ESA hyporesponders, especially those who require high doses, according to Daniel W. Coyne, MD, professor of medicine in the Division of Nephrology at Washington University School of Medicine in St. Louis (MO). Coyne says that the drug's impact as an oral agent would have been much greater had the FDA allowed its use in patients before they reached the dialysis stage because giving injections to dialysis patients is not a barrier to the use of ESAs. In addition, the requirement that patients are established on dialysis means that most of them will have already been started on an ESA if they need treatment for anemia. There will be little reason to change the drug regimen for those who respond to an ESA, so daprodustat will not be a front-line treatment, Coyne explains.

Both ESAs and HIF-PHIs aim to increase the levels of erythropoietin, but the HIF-PHIs have a less direct mechanism of action. By stabilizing the HIF, the drugs inhibit the oxygen pathway to induce a “pseudo-hypoxic” state and work by mimicking the body's reaction to the lower oxygen levels encountered at high altitude to increase erythropoietin. The approach is designed to avoid the supraphysiological peaks in erythropoietin production seen with exogenous ESA use.

The hope that this different mechanism of action might lessen the risk of major adverse cardiovascular events associated with ESAs has not panned out, as shown by the experience with roxadustat and vadadustat. Coyne noted, however, that these two drugs have been approved for use in China, Japan, and many parts of the European Union based on the same safety data that the FDA cited in turning them down.

Coyne said that many nephrologists may regard daprodustat skeptically because of the safety record of the other drugs in its class. “I believe some nephrologists will want to wait and see what happens with this class of drugs because we need longer term safety data given that the drugs affect a large number of genes to a variable amount. Only time will tell whether daprodustat is safer, as safe, or inferior to the ESAs that we are using now,” Coyne said.

Manufacturer GlaxoSmithKline will market daprodustat under the brand name Jesduvroq. “Jesduvroq has a boxed warning for an increased risk of thrombotic vascular (blood clotting) events including death, heart attack, stroke, and blood clots in the lungs, legs, or dialysis access site,” the FDA noted in its press release (1). Daprodustat should not be used by patients with uncontrolled blood pressure, and the most common side effects include high blood pressure, thrombotic vascular events, abdominal pain, dizziness, and allergic reactions.