Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis

Singh, Ajay K.; Carroll, Kevin; McMurray, John J.V.; Solomon, Scott D.; Jha, Vivekanand; Johansen, Kirsten L.; Lópes, Renato D.; Macdougall, Iain C.; Obrador, Gregorio T.; Waikar, Sushrut S.; Wanner, Christoph; Wheeler, David C.; Wiȩcek, Andrzej; Blackorby, Allison; Čižman, Borut; Cobitz, Alexander R.; Davies, Rosalyn; DiMino, Tara; Kler, Lata; Meadowcroft, Amy; Taft, Lin; Perkovic, Vlado

doi:10.1056/nejmoa2113380

Cited by 150 publications

(148 citation statements)

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“…The outcomes of iron metabolism, including changes in hepcidin, TSAT, ferritin, TIBC and total iron are investigated in all the studies. In NDD-CKD patients ( Holdstock et al, 2019 ; Nangaku et al, 2021 ; Singh et al, 2021a ), daprodustat significantly decreased the level of hepcidin, ferritin, total iron and increased the level of TIBC compared with rhEPO, while no significant difference of TSAT was observed between the two groups. In DD-CKD patients ( Holdstock et al, 2016 ; Meadowcroft et al, 2019 ; Akizawa et al, 2020 ; Singh et al, 2021b ), daprodustat significantly increased TSAT, TIBC and the total iron compared with rhEPO, but hepcidin and ferritin levels were not obviously changed.…”

Section: Resultsmentioning

confidence: 91%

“…13 articles were excluded because they did not include a reference group or the comparisons were inappropriate. In total, 7 RCTs ( Holdstock et al, 2016 ; Holdstock et al, 2019 ; Meadowcroft et al, 2019 ; Akizawa et al, 2020 ; Singh et al, 2021a ; Singh et al, 2021b ; Nangaku et al, 2021 ) involving 7933 participants were included in this meta-analysis. Four studies ( Akizawa et al, 2020 ; Singh et al, 2021a ; Singh et al, 2021b ; Nangaku et al, 2021 ) were phase 3 clinical trials, and the other three ( Holdstock et al, 2016 ; Holdstock et al, 2019 ; Meadowcroft et al, 2019 ) were phase 2 clinical trials.…”

Section: Resultsmentioning

confidence: 99%

“…Seven studies ( Holdstock et al, 2016 ; Holdstock et al, 2019 ; Meadowcroft et al, 2019 ; Akizawa et al, 2020 ; Singh et al, 2021a ; Singh et al, 2021b ; Nangaku et al, 2021 ) made comparisons of changes in hemoglobin level and six studies ( Holdstock et al, 2016 ; Holdstock et al, 2019 ; Meadowcroft et al, 2019 ; Akizawa et al, 2020 ; Singh et al, 2021a ; Nangaku et al, 2021 ) reported the number of patients who met the protocol-defined hemoglobin stopping criteria. In both NDD-CKD and DD-CKD patients, daprodustat showed an effect similar to that of rhEPO on increasing the hemoglobin level ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

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Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

Geng

Chi

et al. 2022

Front. Pharmacol.

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Introduction: Daprodustat, a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), its efficacy and safety remain unclear. Thus, we conducted this meta-analysis aiming at investigating its efficacy and safety on the treatment of patients with chronic kidney disease (CKD)-related anemia.Methods: We systematically searched for relevant studies in PubMed, Embase, Cochrane Library and Clinical Trial Registries databases from inception until December 2021. We selected randomized controlled trials comparing daprodustat with recombinant human erythropoietin (rhEPO) in anemia patients with CKD with or without dialysis.Results: Seven studies including 7933 patients met the inclusion criteria. For both nondialysis-dependent (NDD-) CKD and dialysis-dependent (DD-) CKD patients, the pooled results showed that there was no significant difference in the changes in hemoglobin levels between the daprodustat and rhEPO groups (mean difference (MD) = −0.01, 95% confidence interval (CI) = −0.38, 0.35, p = 0.95; MD = 0.15, 95% CI = −0.29, 0.60, p = 0.50; respectively). In addition, a significant increase in transferrin saturation (TSAT), total iron binding capacity (TIBC) and total iron was observed in daprodustat groups compared with rhEPO groups in DD-CKD patients (p < 0.05). As for safety, the overall frequency of adverse events was similar between the daprodustat and rhEPO groups in DD-CKD patients (relative risk (RR) = 0.99, 95%CI = 0.92, 1.06, p = 0.76), and the trial sequential analysis (TSA) confirmed this result. But for NDD-CKD patients, the incidence of adverse events in the daprodustat groups was significantly higher than that of rhEPO groups (RR = 1.04, 95%CI = 1.01,1.07, p = 0.02), while the TSA corrected this result. No trend of increasing incidence of serious adverse events was found in all daprodustat treated patients, but the TSA could not confirm this result.Conclusion: Although daprodustat was noninferior to rhEPO in correcting anemia in both NDD-CKD and DD-CKD patients, it seemed to have a better effect on optimizing iron metabolism in DD-CKD patients. Daprodustat may be a promising alternative for the treatment of anemia in patients with CKD. However, due to the lack of included studies, future researches are needed to further evaluate the therapeutic effect of daprodustat.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier CRD42021229636.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

Geng

Chi

et al. 2022

Front. Pharmacol.

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“…Unfortunately, retinal hemorrhage and hypersensitivity (rash, dermatitis, urticaria), higher acceptance of antihypertensive medications with increasing systolic blood pressure, fatal and nonfatal myocardial infarction and heart failure exacerbations were reported in the daprodustat group (Meadowcroft et al, 2019;Akizawa et al, 2020b;Tsubakihara et al, 2020;Nangaku et al, 2021a). In two newest published studies (Singh et al, 2021a;Singh et al, 2021b), daprodustat showed a tumor effect in NDD patients while not in DD patients, which has not been reported before. Thus, more trials are awaited with interest and the safety and tolerability of daprodustat remain a problem for its clinical usage.…”

Section: Daprodustat (Gsk-1278863)mentioning

confidence: 85%

“…But this influence faded away with the progression of tubulointerstitial fibrosis and even showed a protective reaction ( Kabei et al, 2018 ). Current Phase 3 studies of CKD anemia for 3 of the leading HIF-PHIs have not been able to demonstrate a reduction in rate of progression of CKD as measured by eGFR, properly because the treatment was employed at advanced CKD stage ( Chen et al, 2019b ; Nangaku et al, 2021b ; Singh et al, 2021a ). Thus, to maximally and accurately utilize its ability to attenuate renal damage, timing of drugging is critical.…”

Section: Potential Appliance Of Hif-phds Inhibitors In Non-anemic Dis...mentioning

confidence: 99%

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

Miao

et al. 2022

Front. Pharmacol.

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Hypoxia inducible factors (HIFs) and their regulatory hydroxylases the prolyl hydroxylase domain enzymes (PHDs) are the key mediators of the cellular response to hypoxia. HIFs are normally hydroxylated by PHDs and degraded, while under hypoxia, PHDs are suppressed, allowing HIF-α to accumulate and transactivate multiple target genes, including erythropoiesis, and genes participate in angiogenesis, iron metabolism, glycolysis, glucose transport, cell proliferation, survival, and so on. Aiming at stimulating HIFs, a group of small molecules antagonizing HIF-PHDs have been developed. Of these HIF-PHDs inhibitors (HIF-PHIs), roxadustat (FG-4592), daprodustat (GSK-1278863), vadadustat (AKB-6548), molidustat (BAY 85-3934) and enarodustat (JTZ-951) are approved for clinical usage or have progressed into clinical trials for chronic kidney disease (CKD) anemia treatment, based on their activation effect on erythropoiesis and iron metabolism. Since HIFs are involved in many physiological and pathological conditions, efforts have been made to extend the potential usage of HIF-PHIs beyond anemia. This paper reviewed the progress of preclinical and clinical research on clinically available HIF-PHIs in pathological conditions other than CKD anemia.

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Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients

et al. 2022

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Key Points Question Is daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, an effective oral alternative to darbepoetin alfa in the treatment of anemia of chronic kidney disease (CKD) in incident dialysis (ID) patients? Findings In this randomized clinical trial of 312 ID patients, daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD; the difference in mean hemoglobin concentration between study arms during the evaluation period was 10.5 g/dL for patients receiving daprodustat and 10.6 g/dL for patients receiving darbepoetin alfa. Meaning The study results suggest that daprodustat represents an oral alternative treatment to a conventional erythropoiesis-stimulating agent in the ID population.

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Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis

Cited by 150 publications

References 13 publications

Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

Efficacy and Safety of Daprodustat Vs rhEPO for Anemia in Patients With Chronic Kidney Disease: A Meta-Analysis and Trial Sequential Analysis

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients

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