Daprodustat (JESDUVROQ): the First Oral Drug for Anemia Due to Chronic Kidney Disease

About 15% of adults in the United States have chronic kidney disease.[1] Patients in the later stages of this disease either require a kidney transplant or depend on dialysis to survive.[2]

People on dialysis often cannot produce enough of the hormone erythropoietin, which is secreted by the kidneys and promotes the production of red blood cells. For this reason, anemia (an insufficient number of red blood cells) is a common comorbidity of dialysis.[3] Patients with anemia may require treatment to boost their red blood cell counts or may need blood transfusions, and they have a reduced quality of life. People with anemia are also at a higher risk of developing heart disease and suffering from symptoms such as fatigue, weakness, shortness of breath, body aches and fast and irregular heartbeats.[4]

In addition to transfusions and iron supplementation, treatment for serious anemia due to chronic kidney disease may include synthetic versions of the hormone erythropoietin, called erythropoiesis-stimulating agents (ESAs), that are administered by intravenous or subcutaneous routes.[5] ESAs, including epoetin alfa (EPOGEN, PROCRIT, and biosimilar [RETACRIT]), darbepoetin alfa (ARANESP) and methoxy polyethylene glycol-epoetin beta (MIRCERA), have been available for the treatment of anemia for over 30 years.

However, these drugs are associated with serious adverse events. ESAs carry a boxed warning, the Food and Drug Administration’s (FDA’s) most prominent warning, that covers increased mortality, stroke, myocardial infarction (heart attacks), blood clots and tumor progression or recurrence.[6] Importantly, the warning states that “no trial has identified a hemoglobin target level, dose … or dosing strategy that does not increase these risks.” Moreover, targeting higher hemoglobin levels than are sufficient to reduce the need for blood transfusions can further increase the risk of death and thrombotic events.

The FDA approved daprodustat (JESDUVROQ), the first approved drug of a new class of medications called hypoxia-inducible factor prolyl hydroxylase inhibitors, in February 2023.[7] Daprodustat stimulates the production of erythropoietin and other proteins that promote red blood cell proliferation. Daprodustat is the first oral treatment for adults with anemia due to chronic kidney disease; the tablets are taken once daily, with doses ranging from 1 to 8 milligrams.[8]

Like ESAs, daprodustat carries a boxed warning for “increased risk of death, myocardial infarction, stroke, venous thromboembolism [blood clots in the veins], and thrombosis of vascular access [the dialysis access port].” However, ESAs are approved for patients both on dialysis and not on dialysis, whereas daprodustat is only approved for chronic kidney disease patients who have been receiving dialysis for at least four months.

Public Citizen’s Health Research Group urged the FDA not to approve daprodustat.[9],[10] Although the overall risks of daprodustat appear be comparable to those of ESAs, the risks of some adverse events are slightly increased, as discussed in more detail later in this article. Moreover, at present not enough is known about potential long-term risks associated with daprodustat.[11],[12] Importantly, although daprodustat offers patients with chronic kidney disease an oral medication to treat anemia, this drug has no other truly unique benefits over ESAs. We therefore designate daprodustat as Do Not Use for Seven Years.

The efficacy of daprodustat

Daprodustat was assessed in two randomized, open-label trials. One trial assessed the safety and efficacy of this drug in patients with anemia due to chronic kidney disease who were not on dialysis; the other trial assessed patients already on dialysis.[13] However, due to safety concerns, daprodustat was not approved for patients not on dialysis,[14] so we only discuss the results of the trial in subjects on dialysis. This trial included 2,964 subjects (average age of 58 years) who had been receiving dialysis for at least three months before the trial started. The subjects received either a daily oral dose of daprodustat or one of two intravenous doses of an ESA (depending on the type of dialysis the patients required).

The results of the trial of patients on dialysis showed no clear clinical benefit of treatment with daprodustat compared with treatment with ESAs. For example, daprodustat was non-inferior to (no worse than) the ESAs in increasing hemoglobin levels (a common anemia measurement). Hemoglobin levels increased by a similar extent in both treatment groups. Furthermore, subjects in both groups required similar numbers of red blood cell transfusions. Importantly, according to the FDA, the results “did not demonstrate any other benefits of daprodustat on how patients feel, function, or survive.”[15]

Safety of daprodustat

The trial also demonstrated that for several safety outcomes, daprodustat was non-inferior to ESAs.[16] For example, the rates of serious adverse events in those who received daprodustat (52.2%) and those who received an ESA (50.7%) were comparable. Moreover, during the 2.5-year follow-up period, major adverse cardiovascular events occurred at similar rates in the group who received daprodustat (25.2%) and those who received an ESA (26.7%).

Although all-cause mortality also was similar in both groups, subjects who had received daprodustat had a slightly higher rate of sudden cardiac death, acute heart attack or heart failure than ESA-treated subjects.[17] Importantly, for daprodustat-treated subjects, the risk of heart failure was higher in those with a history of heart failure (14.5%) than in those with a history of heart failure in the ESA-treated group (11.3%).[18]

Treatment with daprodustat also has been found to damage the lining of the stomach, esophagus or intestines and to cause gastrointestinal bleeding.[19] Overall, this risk was comparable in subjects who received either daprodustat or an ESA, but more subjects in the daprodustat group (3.6%) had serious gastrointestinal bleeding than those in the ESA group (3.1%). Daprodustat, like ESAs, also was associated with worsening hypertension (high blood pressure) and may increase the risk of malignancies.

It is important to note that the daprodustat trial had several shortcomings. Apart from being an open-label study (meaning subjects knew whether they received the new oral drug or continued to be treated with ESA injections), which may have affected the results, several patient groups (such as those with certain heart conditions or cancer) were excluded.[20] These exclusions may have led to lower incidences of cardiovascular adverse events or tumors during the trial.[21] Moreover, longer-term safety data for this new class of drug in a larger group of subjects are essential.[22]

What You Can Do

Based on the currently available data, daprodustat offers no substantial benefits over ESAs and appears to have a slightly worse safety profile. Both daprodustat and ESAs are associated with serious adverse events. Until more information becomes available on whether daprodustat is associated with additional long-term safety concerns compared with ESAs, Public Citizen’s Health Research Group recommends that you do not take daprodustat for treatment of anemia due to chronic kidney disease for seven years.

Because no trial has identified a hemoglobin target level, dose or dosing strategy that does not increase the serious risks associated with both ESAs and daprodustat, your clinician should prescribe the lowest dose sufficient to reduce the need for red blood cell transfusions.
 

References

[1] Food and Drug Administration. FDA briefing document, NDA 216951, drug name: daprodustat; Cardiovascular and Renal Drugs Advisory Committee meeting. October 26, 2022. https://www.fda.gov/media/162521/download. Accessed August 5, 2024.

[2] Food and Drug Administration. FDA approves first oral treatment for anemia caused by chronic kidney disease for adults on dialysis. February 1, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-anemia-caused-chronic-kidney-disease-adults-dialysis. Accessed August 5, 2024.

[3] Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385(25):2325-2335.

[4] Doggrell SA. Are there advantages of daprodustat over erythropoiesis-stimulating agents (ESAs) in treating anemia associated with chronic kidney disease (CKD)? Expert Opin Pharmacother. 2022;23(7):769-773

[5] Food and Drug Administration. FDA briefing document, NDA 216951, drug name: daprodustat; Cardiovascular and Renal Drugs Advisory Committee meeting. October 26, 2022. https://www.fda.gov/media/162521/download. Accessed August 15, 2024.

[6] Amgen. Label: epoetin alfa (EPOGEN). September 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103234s5363s5366lbl.pdf. Accessed August 6, 2024.

[7] Food and Drug Administration. FDA briefing document, NDA 216951, drug name: daprodustat; Cardiovascular and Renal Drugs Advisory Committee meeting. October 26, 2022. https://www.fda.gov/media/162521/download. Accessed August 5, 2024.

[8] GlaxoSmithKline. Label: daprodustat (JESDUVROQ). August 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d82aa06e-5a33-4844-99b7-4701313455a4&type=display. Accessed August 5, 2024.

[9] Public Citizen. Testimony before the FDA’s Cardiovascular and Renal Drugs Advisory Committee regarding daprodustat for the treatment of anemia due to chronic kidney disease. October 26, 2022. https://www.citizen.org/article/testimony-before-the-fdas-cardiovascular-and-renal-drugs-advisory-committee-regarding-daprodustat-for-the-treatment-of-anemia-due-to-chronic-kidney-disease/. Accessed on August 5, 2024.

[10] Public Citizen. Letter to the FDA opposing approval of daprodustat and other hypoxia-inducible factor prolyl hydroxylase inhibitors. December 14, 2022. https://www.citizen.org/wp-content/uploads/2649.pdf. Accessed August 5, 2024.

[11] Doggrell SA. Are there advantages of daprodustat over erythropoiesis-stimulating agents (ESAs) in treating anemia associated with chronic kidney disease (CKD)? Expert Opin Pharmacother. 2022;23(7):769-773.

[12] Macdougall IC. Hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors: ready for primetime? Curr Opin Nephrol Hypertens. 2022;31(5):399-405.

[13] Food and Drug Administration. FDA briefing document, NDA 216951, drug name: daprodustat; Cardiovascular and Renal Drugs Advisory Committee meeting. October 26, 2022. https://www.fda.gov/media/162521/download. Accessed August 1, 2024.

[14] GlaxoSmithKline. Label: daprodustat (JESDUVROQ). August 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d82aa06e-5a33-4844-99b7-4701313455a4&type=display. Accessed August 6, 2024.

[15] Food and Drug Administration. FDA briefing document, NDA 216951, drug name: daprodustat; Cardiovascular and Renal Drugs Advisory Committee meeting. October 26, 2022. https://www.fda.gov/media/162521/download. Accessed August 1, 2024.

[16] Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385(25):2325-2335.

[17] Food and Drug Administration. FDA briefing document, NDA 216951, drug name: daprodustat; Cardiovascular and Renal Drugs Advisory Committee meeting. October 26, 2022. https://www.fda.gov/media/162521/download. Accessed August 5, 2024.

[18] GlaxoSmithKline. Label: daprodustat (JESDUVROQ). August 2023.https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d82aa06e-5a33-4844-99b7-4701313455a4&type=display. Accessed Augus 6, 2024.

[19] Ibid.

[20] Food and Drug Administration. FDA briefing document, NDA 216951, drug name: daprodustat; Cardiovascular and Renal Drugs Advisory Committee meeting. October 26, 2022. https://www.fda.gov/media/162521/download. Accessed August 1, 2024.

[21] Doggrell SA. Are there advantages of daprodustat over erythropoiesis-stimulating agents (ESAs) in treating anemia associated with chronic kidney disease (CKD)? Expert Opin Pharmacother. 2022;23(7):769-773.

[22] Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385(25):2325-2335.