Daprodustat (Jesduvroq)
March 15, 2023
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first oral treatment for anemia caused by chronic kidney disease (CKD) in adults on dialysis. Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor that promotes the secretion of endogenous erythropoietin and resultant production of red cells. HIF plays a pivotal role in regulating erythropoiesis. Current parenteral erythropoiesis-stimulating agents (ESA) include epoetin alfa, darbepoetin alfa, and methoxy PEG-epoetin beta. Daprodustat is marketed as Jesduvroq.
INDICATIONS
Daprodustat can be prescribed to treat anemia caused by CKD in adults who have been receiving dialysis for at least four months.1
DOSAGE
For patients not taking an ESA, the starting dose is based on pretreatment hemoglobin levels. For levels lower than 9 g/dL, the dose is 4 mg once daily. For levels 9 g/dL or higher to 10 g/dL or lower, the dose is 2 mg once daily. For levels higher than 10 g/dL, the dose is 1 mg once daily. For those switching from an ESA, the dose of daprodustat is based on the current dose of ESA.1 The starting dose should be cut by half (except the 1 mg dose) when initiating treatment on clopidogrel or a moderate CYP2C8 inhibitor.1 Hemoglobin levels should be monitored and dosage adjusted as needed when initiating or stopping therapy with clopidogrel or a moderate CYP2C8 inhibitor.
After treatment initiation and after each dose adjustment, hemoglobin should be monitored every two weeks for the first month, and every four weeks thereafter. Daprodustat can be taken once daily with or without food. It available as 1 mg, 2 mg, 4 mg, 6 mg, and 10 mg tablets.
POTENTIAL ADVANTAGES
Daprodustat provides a more convenient oral option than the current ESAs, which require subcutaneous or intravenous administration.
POTENTIAL DISADVANTAGES
The long-term safety of daprodustat is unknown. The results of a meta-analysis of 13,146 patients suggested an increased risk of thrombosis events vs. ESAs.2 Daprodustat shares the same warning as other ESAs for higher risk of thrombotic vascular events, including major adverse cardiovascular events (MACE).1 Concomitant administration with a strong CYP2C8 inhibitor is contraindicated. The drug is not approved for CKD patients who are not on dialysis.
COMMENTS
Daprodustat is a reversible inhibitor of oxygen-sensing PH enzymes, which stabilizes HIF, triggers stimulation of endogenous erythropoietin, and optimizes iron use that corrects anemia, similar to the physiological response that occurs at high altitude.3 It produces new hemoglobin steady-state levels in approximately four weeks in ESA-users and in 16 to 20 weeks in ESA nonusers after treatment initiation.1
The efficacy and safety of daprodustat were evaluated in an open-label, randomized, active-controlled, event-driven trial in patients with CKD who were undergoing dialysis for at least four months.1,4 Subjects recorded mean hemoglobin levels of 10.4 g/dL. At randomization, 88.6% were on hemodialysis (HD) and 11.4% were on peritoneal dialysis (PD). Subjects on HD were randomized to either daprodustat (n = 1,316) or intravenous epoetin alfa (n = 1,308). Those on PD were randomized to daprodustat (n = 171) or subcutaneous darbepoetin alfa (n = 169). The starting dose of daprodustat was 4 mg, 6 mg, 8 mg, or 12 mg, based on prior ESA dose. The starting dose of epoetin alfa or darbepoetin alfa was the same as the patient’s current dose, rounded to the nearest study dose. Those on other ESAs switched to equivalent dose of study ESAs.
There were two primary noninferiority efficacy endpoints: the mean change in hemoglobin from baseline to the evaluation period (week 28 to week 52) and time to first adjudicated MACE. This was defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke. Daprodustat was noninferior to ESAs in terms of change in hemoglobin levels as well as MACE outcomes. The difference between daprodustat and ESA users was 0.18 g/dL (95% CI, 0.12-0.24), meeting the authors’ prespecified noninferiority margin of -0.75 g/dL.
After a median follow-up of 2.5 years, the rates of MACE were 25.2% in the daprodustat group and 26.7% for ESAs (HR, 0.93; 95% CI, 0.81-1.07). The frequency of reported adverse reactions between groups were similar.1,2 These included hypertension, abdominal pain, dizziness, and hypersensitivity (e.g., rash, urticaria, dermatitis).
CLINICAL IMPLICATIONS
Approximately 500,000 adults in the United States are living with CKD that requires dialysis.5 Daprodustat is an inhibitor of HIF PH, and is the first approval in a novel class of oral medicines for the treatment of anemia of CKD in adult patients on dialysis. Two other HIF PH inhibitors (roxadustat, vadadustat) have been rejected by the FDA because of safety concerns.6,7 Daprodustat provides a more convenient oral alternative to other ESAs, with comparable efficacy and safety profile. However, long-term safety has not been established. Cost was unavailable at the time of this review.
REFERENCES
1. GSK plc. Jesduvroq prescribing information. February 2023.
2. Chen H, Cheng Q, Wang J, et al. Long-term efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in anaemia of chronic kidney disease: A meta-analysis including 13,146 patients. J Clin Pharm Ther 2021;46:999-1009.
3. Hasse VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev 2013;27:41-53.
4. Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med 2021;385:2325-2335.
5. U.S. Food & Drug Administration. FDA approves first oral treatment for anemia caused by chronic kidney disease for adults on dialysis. Feb. 1, 2023.
6. AstraZeneca. Status on FDA advisory committee vote on roxadustat in anaemia of chronic kidney disease. July 16, 2021.
7. Akebia Therapeutics. Akebia Therapeutics receives complete response letter from the FDA for vadadustat for the treatment of anemia due to chronic kidney disease in adult patients. March 30, 2022.
Daprodustat can be prescribed to treat anemia caused by chronic kidney disease in adults who have been receiving dialysis for at least four months.
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