Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis

Chen, Nan; Hao, Chuan‐Ming; Liu, Bi‐Cheng; Lin, Hongli; Wang, Caili; Xing, Changying; Liang, Xinling; Jiang, Gengru; Liu, Zhengrong; Li, Xuemei; Zuo, Li; Luo, Liulin; Wang, Jianqin; Zhao, Minghui; Liu, Zhihong; Cai, Guangyan; Li, Hao; Leong, Robert; Wang, Chunrong; Liu, Cameron; Neff, Thomas B.; Szczech, Lynda A.; Yu, Kin-Hung Peony

doi:10.1056/nejmoa1901713

Cited by 465 publications

(625 citation statements)

References 31 publications

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“…The positive effects of HIF prolyl hydroxylase inhibitors (that is, HIF activators) over anemia and other cardiovascular risk parameters in CKD patients [95] raises the possibility that downregulation of HIF activation righter than loss of renal mass is a key driver of uremic anemia and may allow the exploration of the chronodisruption impact of uremic anemia itself.…”

Section: Disrupted Hif Activation and Epo Productionmentioning

confidence: 99%

Chronodisruption: A Poorly Recognized Feature of CKD

Carriazo

Ramos

Sanz

et al. 2020

Toxins

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Multiple physiological variables change over time in a predictable and repetitive manner, guided by molecular clocks that respond to external and internal clues and are coordinated by a central clock. The kidney is the site of one of the most active peripheral clocks. Biological rhythms, of which the best known are circadian rhythms, are required for normal physiology of the kidneys and other organs. Chronodisruption refers to the chronic disruption of circadian rhythms leading to disease. While there is evidence that circadian rhythms may be altered in kidney disease and that altered circadian rhythms may accelerate chronic kidney disease (CKD) progression, there is no comprehensive review on chronodisruption and chronodisruptors in CKD and its manifestations. Indeed, the term chronodisruption has been rarely applied to CKD despite chronodisruptors being potential therapeutic targets in CKD patients. We now discuss evidence for chronodisruption in CKD and the impact of chronodisruption on CKD manifestations, identify potential chronodisruptors, some of them uremic toxins, and their therapeutic implications, and discuss current unanswered questions on this topic.

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Section: Disrupted Hif Activation and Epo Productionmentioning

confidence: 99%

Chronodisruption: A Poorly Recognized Feature of CKD

Carriazo

Ramos

Sanz

et al. 2020

Toxins

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“…After four-week roxadustat treatment, hepcidin levels significantly decreased in all patient cohorts [110]. Recently, roxadustat has undergone two phase three trials in China undertaken with CDK patients who displayed an increase in haemoglobin levels above those of the controls [140,141]. Lastly, daproustat a competitive reversible inhibitor of PHDs through its interactions with the catalytic iron and subsequent blocking of substrate entry [142] has also been tested as a hepcidin targeting molecule.…”

Section: Hypoxia-inducible Factors (Hif) Stabilisersmentioning

confidence: 99%

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

et al. 2019

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The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways.

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“…Roxadustat has previously demonstrated efficacy and tolerability in phase 2 studies in patients with dialysis-dependent (DD) [9][10][11] and NDD [10,[12][13][14] anemia of CKD. Phase 3 studies conducted in China [15,16] and Japan [17] have demonstrated roxadustat's efficacy and safety in both DD-CKD and NDD-CKD patients, and roxadustat has recently been approved in China in DD and NDD patients and in Japan in DD patients. Development is ongoing in Europe, Japan (NDD only), the USA, and other countries in DD and NDD patients [15][16][17].This study investigated the efficacy and safety of oral roxadustat administered at 2 different initial doses and titrated to achieve and maintain target Hb levels in Japanese ESA-naïve NDD-CKD patients with renal anemia.…”

Section: Introductionmentioning

confidence: 99%

A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis

Akizawa

Yamaguchi

Otsuka

et al. 2020

Nephron

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Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia in Japan for patients with dialysis-dependent (DD) chronic kidney disease (CKD). Objective: Multicenter, randomized, open-label, noncomparative, phase 3 study to evaluate roxadustat for anemia of non-dialysis-dependent (NDD) CKD in Japan. Methods: Erythropoiesis stimulating agent (ESA)-naïve NDD-CKD patients were randomized to roxadustat (initial dose, 50 or 70 mg 3 times weekly), titrated to maintain hemoglobin (Hb) within 10.0-12.0 g/dL, for ≤24 weeks. Patients with either transferrin saturation of ≥5% or serum ferritin of ≥30 ng/mL during the screening period were eligible. Endpoints included response rate (proportion of patients achieving Hb ≥10.0 or ≥10.5 g/dL and Hb increase ≥1.0 g/dL from baseline) at end of treatment; average Hb (weeks 18-24); change of average Hb from baseline to weeks 18-24; maintenance rate (proportion of patients achieving Hb 10.0-12.0 g/dL at weeks 18-24); rate of rise (RoR) of Hb from weeks 0-4, discontinuation, or dose adjustment. Adverse events were monitored throughout the study. Results: Of 135 patients who provided informed consent, 100 were randomized and 99 received roxadustat (50 mg, n = 49; 70 mg, n = 50). The mean (SD) dose of roxadustat per intake at week 22 was 36.3 (22.7) mg in the roxadustat 50 mg group and 36.8 (16.0) mg in the roxadustat 70 mg group. Prior medications included oral iron therapy (20.2%) and intravenous iron therapy (1.0%). Overall response rate (95% CI) was 97.0% (91.4, 99.4; Hb ≥10.0 g/dL) and 94.9% (88.6, 98.3; Hb ≥10.5 g/ dL). Mean (SD) Hb (weeks 18-24) was 11.17 (0.62) g/dL. Mean (SD) change of Hb from baseline (weeks 18-24) was 1.34 (0.86) g/dL. Maintenance rate (95% CI) was 88.8% (80.3, 94.5) among patients with ≥1 Hb measurement during weeks 18-24. Mean (SD) RoR of Hb was 0.291 (0.197) g/dL/week (50 mg) and 0.373 (0.235) g/dL/week (70 mg). Nasopharyngitis and hypertension were the most common adverse events. Conclusion: Roxadustat increased and maintained Hb in ESA-naïve, partially iron-depleted NDD-CKD patients with anemia.

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Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis

Cited by 465 publications

References 31 publications

Chronodisruption: A Poorly Recognized Feature of CKD

Chronodisruption: A Poorly Recognized Feature of CKD

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis

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