SaO036Efficacy and safety of daprodustat compared with darbepoetin alfa in Japanese hemodialysis patients with anemia: a randomized, double-blind, phase 3 trial

Akizawa, Tadao; Nangaku, Masaomi; Yonekawa, Taeko; Okuda, Nobuhiko; Kawamatsu, Shinya; Onoue, Tomohiro; Endo, Yutaka; Hara, Katsutoshi; Ozeki, Hirofumi; Cobitz, Alexander R.

doi:10.1093/ndt/gfz101.sao036

Cited by 23 publications

(52 citation statements)

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“…121 Some phase 2 studies included patients who received placebo for a limited time period of 4 to 6 weeks. 112,[115][116][117][118] Clinical efficacy data from phase 3 trials for daprodustat, 13,14 enarodustat, 77 molidustat, 95 roxadustat, [16][17][18]22,90,[96][97][98] and vadadustat 20,99 are summarized in Table 3. Noninferiority to darbepoetin alfa with regard to maintaining target Hb was reported for daprodustat (n ¼ 271), 14 enarodustat (n ¼ 173), 77 molidustat (n ¼ 229), 95 and vadadustat, in both a study of maintenance hemodialysis patients (n ¼ 323) 20 and the INNO2VATE studies of patients on incident (n ¼ 369) and c l i n i c a l i n v e s t i g a t i o n VH Haase: HIF-PH inhibitors for anemia of CKD maintenance (n ¼ 3554) hemodialysis.…”

Section: Dialysis-dependent Ckdmentioning

confidence: 99%

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

Haase

2021

Kidney International Supplements

101

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Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a promising new class of orally administered drugs currently in late-stage global clinical development for the treatment of anemia of chronic kidney disease (CKD). HIF-PHIs activate the HIF oxygen-sensing pathway and are efficacious in correcting and maintaining hemoglobin levels in patients with non-dialysis-and dialysis-dependent CKD. In addition to promoting erythropoiesis through the increase in endogenous erythropoietin production, HIF-PHIs reduce hepcidin levels and modulate iron metabolism, providing increases in total iron binding capacity and transferrin levels, and potentially reducing the need for i.v. iron supplementation. Furthermore, HIF-activating drugs are predicted to have effects that extend beyond erythropoiesis. This review summarizes clinical data from current HIF-PHI trials in patients with anemia of CKD, discusses mechanisms of action and pharmacologic properties of HIF-PHIs, and deliberates over safety concerns and potential impact on anemia management in patients with CKD.

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Section: Dialysis-dependent Ckdmentioning

confidence: 99%

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

Haase

2021

Kidney International Supplements

101

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“…In haemodialysis patients with anaemia of CKD who were treated with ESAs (NCT02969655), the most frequent (incidence ≥ 10%) treatment-emergent AEs with daprodustat or darbepoetin alfa during 52 weeks' therapy were nasopharyngitis, diarrhoea, shunt stenosis, contusion and vomiting [16]. Most treatment-emergent AEs were of mild or moderate severity and no deaths were reported in the study.…”

Section: Adverse Eventsmentioning

confidence: 95%

“…Daprodustat was noninferior to darbepoetin alfa in maintaining target Hb levels (10-12 g/dL) in Japanese haemodialysis patients with anaemia of CKD who were treated with ESAs, according to results of a randomized, double-blind, multicentre, phase 3 study (NCT02969655) [16]. Eligible patients were randomized to receive titration algorithm-determined dosages of daprodustat (n = 136) or darbepoetin alfa (n = 135) for 52 weeks.…”

Section: Features and Properties Of Daprodustatmentioning

confidence: 99%

“…During weeks 40-52 of treatment, the mean Hb level in patients receiving daprodustat was noninferior to that in patients receiving darbepoetin alfa (10.89 vs. 10.83 g/dL; primary endpoint), as the lower limit of 95% confidence interval was greater than the pre-specified noninferiority margin of − 1.0 g/dL (between-group difference 0.06 g/dL; 95% CI − 0.11 to 0.23). The majority of patients receiving daprodustat (88%) or darbepoetin alfa (90%) had Hb levels within the target range over weeks 40-52 of therapy [16].…”

Section: Features and Properties Of Daprodustatmentioning

confidence: 99%

“…Daprodustat was generally well tolerated in the phase 3 studies in haemodialysis patients with anaemia of CKD who were (NCT02969655) [16] or were not (NCT02829320) [15] treated with an ESA, as well as in non-dialysis-dependent and peritoneal dialysis patients with anaemia of CKD (NCT02791763) [7]. Adverse reactions reported with daprodustat include retinal haemorrhage, hypersensitivity (rash, dermatitis, urticaria) and high blood pressure (BP) [all < 1% in frequency].…”

Section: Adverse Eventsmentioning

confidence: 99%

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Daprodustat: First Approval

Dhillon

2020

Drugs

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Daprodustat (DUVROQ) is a small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (PHD) developed by GlaxoSmithKline for the treatment of anaemia in patients with chronic kidney disease (CKD). Inhibition of PHD prevents degradation of hypoxia-inducible factor (HIF), leading to the production of erythropoietin and subsequent induction of erythropoiesis. In June, daprodustat received its first approval in Japan for the treatment of renal anaemia. Clinical studies of daprodustat are underway in multiple countries worldwide. This article summarizes the milestones in the development of daprodustat leading to this first approval for the treatment of renal anaemia.

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Pharmacokinetics of Daprodustat and Metabolites in Individuals with Normal and Impaired Hepatic Function

Mahar

Shaddinger

Ramanjineyulu

et al. 2022

Clinical Pharm in Drug Dev

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Daprodustat is a hypoxia‐inducible factor‐prolyl hydroxylase inhibitor in development for treatment of anemia of chronic kidney disease. We evaluated the role of hepatic impairment on daprodustat pharmacokinetics, pharmacodynamics, and tolerability. Participants with mild (Child‐Pugh Class A, score 5‒6) and moderate (Child‐Pugh Class B, score 7‒9) hepatic impairment and matched healthy controls were administered single 6‐mg doses of daprodustat. Exposure parameters were determined for daprodustat and its six metabolites. Comparisons resulted in 1.5‐ and 2.0‐fold higher daprodustat Cmax and area under the curve (AUC) exposures in participants with mild and moderate hepatic impairment, respectively, versus controls; Cmax in mild hepatic impairment was comparable to controls. Similarly, aligned with parent drug, unbound daprodustat Cmax and AUC exposures increased 1.6‐ to 2.3‐fold in hepatic‐impaired participants versus controls, and metabolite exposures were 1.2‐ to 2.0‐fold higher in participants with hepatic impairment. Erythropoeitin (EPO) baseline‐corrected AUC exposures were between 0.3‐fold lower and 2.2‐fold higher in matched controls versus hepatic‐impaired participants. No serious or study drug‐related adverse events were reported. Daprodustat exposure was increased in participants with moderate and mild hepatic impairment compared with matched controls; however, no meaningful differences in EPO were observed and no new safety concerns were identified (ClinicalTrials.gov: NCT03223337).

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SaO036Efficacy and safety of daprodustat compared with darbepoetin alfa in Japanese hemodialysis patients with anemia: a randomized, double-blind, phase 3 trial

Cited by 23 publications

References 0 publications

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

Daprodustat: First Approval

Pharmacokinetics of Daprodustat and Metabolites in Individuals with Normal and Impaired Hepatic Function

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