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    Daprodustat (Jesduvroq): First oral treatment for anaemia due to CKD in adult dialysis patients

    ShanPingBy

    Burden of disease

    Chronic kidney disease (CKD) is characterised by progressive loss of kidney function. Anaemia is a frequent complication of CKD and is associated with increased morbidity, mortality, higher healthcare costs and reduced quality of life.1–3 Over 700 million patients suffer from CKD globally and an estimated 1 in 7 of these patients have anaemia.4 CKD affects over 300,000 patients in Singapore, of whom approximately one-third have anaemia.5,6 

    The mechanisms involved in anaemia associated with CKD are diverse and complex. They include a decrease in endogenous erythropoietin (EPO) production, absolute and/or functional iron deficiency, and inflammation with increased hepcidin levels, among others. Patients are most commonly managed with oral or intravenous iron supplements and with erythropoiesis-stimulating agents (ESA). However, these treatments have associated risks (e.g., cardiovascular events, venous thromboembolism, tumour progression or death)7,8, and are sometimes insufficiently effective. When left untreated or undertreated, anaemia of CKD is associated with poor clinical outcomes and leads to a substantial burden on patients and healthcare systems.

    US FDA approval of daprodustat

    In February 2023, the US FDA approved daprodustat (Jesduvroq), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), for the treatment of anaemia due to CKD in adults who have been receiving dialysis for at least 4 months.9 The regulatory approval represents the first innovative therapy for the treatment of anaemia in over 3 decades, providing a convenient oral therapeutic option for patients with anaemia of CKD on dialysis. Inhibition of oxygen-sensing prolyl hydroxylase enzymes stabilises hypoxia-inducible factors, which can lead to transcription of erythropoietin and other genes involved in the correction of anaemia, similar to the physiological effects that occur in the human body at high altitude.10,11 HIF prolyl hydroxylase inhibitors also influence iron homeostasis through effects on transferrin, transferrin receptor expression, hepcidin, and other iron-related proteins.10,11

    US FDA approval was based primarily on results from the ASCEND-D cardiovascular outcomes trial (CVOT) which included 2,964 dialysis patients with anaemia of CKD who were switched to receive daprodustat ESA control from a standard of care ESA therapy.9,12 ASCEND-D was part of the larger ASCEND Phase III clinical trial programme that included 5 Phase III trials assessing the efficacy and safety profile of daprodustat for the treatment of anaemia of CKD across the disease spectrum. The programme enrolled over 8,000 patients who were treated for up to 4.26 years. In all 5 trials, the drug met its primary efficacy endpoint, showing an improvement in Hb levels in treated participants. 

    ASCEND-D: efficacy and safety outcomes 

    A summary of ASCEND-D is described in the table below. Adults with CKD who had been undergoing dialysis for at least 90 days, had received an ESA for at least 6 weeks, and who had a haemoglobin level between 8.0 and 12.0 g/dL were eligible for screening. 

    Patients were also required to have a serum ferritin level of more than 100 ng/mL and a transferrin saturation above 20%. Patients underwent randomization in a 1:1 ratio to receive either oral daprodustat or an injectable ESA (intravenous epoetin alfa among those receiving hemodialysis and subcutaneous darbepoetin alfa among those receiving peritoneal dialysis). A uniform iron management protocol was instituted across both arms of the study. 

    Efficacy results showed that daprodustat improved and maintained haemoglobin (Hb) within target levels of 10-11.5 g/dL, and the primary safety analysis of the intention-to-treat (ITT) population showed that daprodustat achieved non-inferiority of MACE compared to ESA control.12 

    Table 1 ASCEND-D Trial Outcomes 12

    Population N=2,964 total of which N=1,487 received daprodustat and N=1,477 received ESA

    • 88.5% were undergoing haemodialysis and 12.2% were considered to have ESA hypo-responsiveness.
    • The mean baseline Hb level was 10.4±1.0 g/dL across the 2 groups
    Primary efficacy endpoint
    • The mean (±SE) change in the Hb level from baseline to weeks 28 through 52 was 0.28±0.02 g/dL with daprodustat and 0.10±0.02 g/dL with ESA therapy, for a difference of 0.18 g/dL (95%CI, 0.12 to 0.24), which met the prespecified noninferiority margin for daprodustat
    Primary safety outcome
    • A first major adverse cardiovascular event (MACE) occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 patients (26.7%) in the ESA group (HR, 0.93; 95% CI, 0.81 to 1.07), results that met the prespecified noninferiority margin of 1.25
    Secondary outcomes
    • The results of superiority testing for daprodustat as compared with ESA were not significant regarding the three cardiovascular principal secondary outcomes: 
      • The first occurrence of MACE (HR, 0.93; 95% CI, 0.81 to 1.07)
      • The first occurrence of MACE or a thromboembolic event (HR, 0.88; 95% CI, 0.78 to 1.00)
      • The first occurrence of MACE or hospitalization for heart failure (hazard ratio, 0.97; 95% CI, 0.85 to 1.11) 
    • The incidence of death from any cause was similar in the two groups (HR, 0.96; 95% CI, 0.82 to 1.13)
    • The superiority test for the mean monthly dose of intravenous iron from baseline through week 52, a principal secondary outcome, was also not significant. The mean (±SE) monthly dose from day 1 to week 52 decreased to 90.8±3.3 mg in the daprodustat group and to 99.9±3.3 mg in the ESA group, for a mean difference of −9.1 mg (95% CI, −18.4 to 0.2 mg)
    Adverse events (AEs)
    • Serious AEs during the trial were reported in 773 patients (52.2%) in the daprodustat group and in 748 (50.7%) in the ESA group 
    • The most common AEs observed in the daprodustat group include worsening of hypertension, oesophageal or gastric erosions, and cancer-related death or tumour progression or recurrence 
    • There was no notable excess of any event in the daprodustat group. The incidences of prespecified adverse events of special interest — including oesophagal or gastric erosions and cancers — were similar in the two treatment groups. 
    • Daprodustat had an effect on blood pressure and the use of antihypertensive medications that was similar to that with ESA therapy

    References

    1. Astor BC, Coresh J, Heiss G, Pettitt D, Sarnak MJ. Kidney function and anemia as risk factors for coronary heart disease and mortality: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 2006;151(2):492-500. doi:10.1016/j.ahj.2005.03.055
    2. Moreno F, López Gomez JM, Sanz-Guajardo D, Jofre R, Valderrábano F. Quality of life in dialysis patients. A spanish multicentre study. Spanish Cooperative Renal Patients Quality of Life Study Group. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc – Eur Ren Assoc. 1996;11 Suppl 2:125-129. doi:10.1093/ndt/11.supp2.125
    3. Nissenson AR, Wade S, Goodnough T, Knight K, Dubois RW. Economic burden of anemia in an insured population. J Manag Care Pharm. 2005 Sep;11(7):565-74. doi: 10.18553/jmcp.2005.11.7.565. PMID: 16137214.
    4. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Lond Engl. 2020;395(10225):709-733. doi:10.1016/S0140-6736(20)30045-3
    5. Lau BCV, Ong KY, Yap CW, Vathsala A, How P. Predictors of anemia in a multi-ethnic chronic kidney disease population: a case–control study. SpringerPlus. 2015;4:233. doi:10.1186/s40064-015-1001-z
    6. Key Statistics – The National Kidney Foundation (NKF) Singapore. Accessed March 19, 2023. https://nkfs.org/about-us/key-statistics/
    7. Babitt JL, Lin HY. Mechanisms of Anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631. doi:10.1681/ASN.2011111078
    8. Research C for DE and. Postmarket Drug Safety Information for Patients and Providers – Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)]. Accessed April 3, 2023. https://wayback.archive-it.org/7993/20170723113601/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126481.htm
    9. JESDUVROQ (daprodustat) Tablets SmPC Issued February 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216951s000lbl.pdf 
    10. Sugahara M, Tanaka T, Nangaku M. Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anemia in chronic kidney disease. Kidney Int. 2017;92(2):306-312. doi:10.1016/j.kint.2017.02.035
    11. Kaplan JM, Sharma N, Dikdan S. Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease. Int J Mol Sci. 2018;19(2):389. doi:10.3390/ijms19020389
    12. Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis | NEJM. Accessed April 3, 2023. https://www.nejm.org/doi/full/10.1056/NEJMoa2113379
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    Shan is a licensed pharmacist working in the acute setting in a restructured hospital in Singapore. With a passion for communicating the technicalities of medicine artfully through the written word, she continues honing her craft through creating purposeful content within the healthcare industry.

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