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First oral agent approved for anemia in patients with CKD receiving dialysis
Kate Setzler 2048

First oral agent approved for anemia in patients with CKD receiving dialysis

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Anemia

Corey Diamond, PharmD

Chronic kidney disease (CKD) is a growing health issue worldwide that impacts approximately 700 million individuals, with nearly 14% of patients with CKD also experiencing anemia. If left unaddressed or not properly treated, anemia resulting from CKD is linked with unfavorable clinical outcomes and imposes a significant strain on both patients and health care systems. Until recently, there has been a need for new oral therapies that are equally as effective and safe as existing treatments.

On February 1, 2023, FDA announced the approval of daprodustat (Jesduvroq—GSK) as the first treatment for anemia in end-stage renal disease that can be taken via the oral route. The medication is currently the only one approved for use in patients who have been receiving dialysis for at least 4 months.

exhausted looking red blood cells

ASCEND-D

The approval of daprodustat was based on the results of the Phase 3 ASCEND-D trial—published by Singh and colleagues in NEJM in November 2021—which included over 2,900 patients with end-stage renal disease on dialysis with anemia. The trial was a randomized, open-label, active-controlled, parallel-group, event-driven study conducted at 431 centers in 35 countries. Participants were randomized to either receive daprodustat or recombinant human erythropoietin (rhEPO) plus a placebo.

The study’s two primary endpoints were time to first occurrence of a major adverse cardiovascular event (i.e., a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke) and the mean change from baseline in hemoglobin levels during the pre-defined evaluation period.

The results of ASCEND-D demonstrated that dialysis patients taking daprodustat had a mean change in hemoglobin of 0.3 g/dL compared to 0.1 g/dL in the rhEPO group, which achieved the goal noninferiority margin of –0.75 g/dL. Additionally, during the 2.5-year major adverse cardiovascular event (MACE) follow-up period, dialysis patients who received daprodustat experienced a MACE event rate of 25.2% versus 26.7% in patients receiving rhEPO, achieving the goal noninferiority margin of 1.25.

Key differences

Patients in end-stage renal disease almost always progress to a state of chronic anemia due to a reduction in kidney function that affects their ability to produce a hormone known as erythropoietin, which signals the body to produce red blood cells.

Currently, the only treatments available for this are protein analogs known as erythropoietin stimulating agents (ESAs). However, their design as hormone analogs makes it difficult to formulate an oral option. ESAs are only available via I.V. and S.C. routes.

Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). HIF-PHIs inhibit oxygen-sensing prolyl hydroxylase enzymes which, in turn, stabilizes hypoxia-inducible factors. This process mimics the mechanism in the human body at high altitudes and is theorized to increase the transcription of erythropoietin in the kidneys. Its chemical structure also allows it to be delivered, conveniently, through the oral route.

“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 Ann Farrell, MD, director of the Division of Non-Malignant Hematology in FDA’s Center for Drug Evaluation and Research in an FDA news release. “This approval demonstrates FDA’s commitment to helping bring a range of therapeutic options to patients with chronic diseases. Patients can consult with their health care providers to select the option that is most appropriate.”

Safety and warnings

While the mechanism of daprodustat may be novel, the ASCEND-D trial did not provide sufficient evidence to suggest that its adverse effect profile is safer than ESAs.

Similar to ESAs, daprodustat contains a boxed warning for increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access. Additionally, likewise to ESAs, targeting a hemoglobin level >11 g/dL with daprodustat is expected to confer similar risk of death and arterial venous thrombotic events.

No trial has yet to identify a daprodustat dosing strategy that does not increase these risks; thus, the lowest dose of daprodustat should be used to achieve therapy goals. ■

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