Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis

Chen, Nan; Hao, Chuan‐Ming; Peng, Xiaomei; Lin, Hongli; Yin, Aiping; Li, Hao; Tao, Ye; Liang, Xinling; Liu, Zhengrong; Xing, Changying; Chen, Jianghua; Luo, Liulin; Zuo, Li; Liao, Yunhua; Liu, Bi‐Cheng; Leong, Robert; Wang, Chunrong; Liu, Cameron; Neff, Thomas B.; Szczech, Lynda A.; Yu, Kin-Hung Peony

doi:10.1056/nejmoa1813599

Cited by 461 publications

(519 citation statements)

References 31 publications

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“…Future studies will need to investigate whether novel agents to treat anemia such as inhibitors of hypoxiainducible factor are a safe and effective alternatives to transfusion. 28 We describe how ESAs have been deimplemented in oncology as the impact of safety findings and policy changes among privately insured cancer patients with CIA have resulted in an estimated a 90-95% decrease in the number of privately insured cancer patients with CIA who receive darbepoetin or epoetin. This mechanism for reduction in ESA use can be used as an example of how to successfully deimplement agents in clinical practice to improve patient safety.…”

Section: Resultsmentioning

confidence: 99%

“…This has resulted in the increased use of red blood cell transfusion, which also carries risk of adverse events. Future studies will need to investigate whether novel agents to treat anemia such as inhibitors of hypoxia‐inducible factor are a safe and effective alternatives to transfusion 28 . We describe how ESAs have been deimplemented in oncology as the impact of safety findings and policy changes among privately insured cancer patients with CIA have resulted in an estimated a 90–95% decrease in the number of privately insured cancer patients with CIA who receive darbepoetin or epoetin.…”

Section: Discussionmentioning

confidence: 99%

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End of an era for erythropoiesis‐stimulating agents in oncology

Schoen

Hoque

Witherspoon

et al. 2020

Intl Journal of Cancer

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Erythropoiesis‐stimulating agents (ESAs) are available to treat chemotherapy‐induced anemia (CIA). In 2007–2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin <10 g/dl. In 2010, a Risk Evaluation and Mitigation Strategies required consent prior to administration. We evaluated ESA utilization from 2003 to 2012 and obtained private health insurer claims data for persons with lung, colorectal, or breast cancer from 2001 to 2012. ESA use for CIA was determined by an ESA claim after chemotherapy, up to 6 months after treatment. We identified 839,948 commercially insured patients, including 24,785 patients with ESA‐treated CIA (3.2%). Darbepoetin use increased 3.9‐fold from 2003 to 2007 (12.3% to 48.7%) and then decreased 95% to 2.6% by 2012. Epoetin use decreased 90% from 2003 to 2012 (30.3% to 3.1%). Between 2003 and 2012, mean epoetin dosing decreased 0.8‐fold (244,979 in 2003 vs. 196,216 units in 2012), but increased 1.8‐fold for darbepoetin‐treated CIA (262 in 2003 to 467 μg in 2012). Among CIA patients, transfusions were low (4.5%) in 2002–2007, then increased 2.2‐fold between 2008 and 2012. Safety initiatives between 2007 and 2010 facilitated reductions in ESA use combined with changes in coverage. These data show the efficacy of regulatory efforts, publication of adverse events and changes in reimbursement in reducing use of ESAs. Future studies are warranted to optimize deimplementation strategies to improve patient safety.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

End of an era for erythropoiesis‐stimulating agents in oncology

Schoen

Hoque

Witherspoon

et al. 2020

Intl Journal of Cancer

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“…The finding by Kaelin and Ratcliffe that PHD inhibitors based on 2OG analogues stabilise HIFα in normoxia and induce HIF target genes established the PHDs as bona fide pharmacological targets . The numerous patents on HIF hydroxylase inhibitors resulted in several compounds in late‐stage clinical trials; this year the clinical efficacy of Roxadustat in the treatment of anaemia was reported …”

Section: Therapeutic Relevance and A Second Hif Hydroxylasementioning

confidence: 99%

An Oxygen Sensation: Progress in Macromolecule Hydroxylation Triggered by the Elucidation of Cellular Oxygen Sensing

Loenarz

2020

Angew Chem Int Ed

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The 2019 Nobel Prize in Physiology or Medicine honours three scientists that devoted their careers to pursuing an audacious basic science question: by what mechanisms do animals sense oxygen, and how can cells adapt to a lack of oxygen? The identification of the human hypoxia inducible factor pathway has enabled new approaches for the therapy of related diseases including cancer, cardiovascular disease, anaemia, and stroke. The intricate molecular details of oxygen sensing broadened interest in the family of iron‐ and 2‐oxoglutarate‐dependent oxygenases known from elaborate natural product chemistry, and catalysed major progress in macromolecule hydroxylation. The laureates’ work enables numerous avenues for molecular scientists, from C−H activation chemistry to PROTAC technology, medicinal chemistry, and epigenetics.

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“…Die Eignung der Prolylhydroxylasen als therapeutisches Target konnte durch Kaelin und Ratcliffe gezeigt werden: Eine Inhibition der PHDs durch 2‐Oxoglutarat‐Analoga resultiert in einer Stabilisierung von HIF, was wiederum zu einer erhöhten Expression von HIF‐induzierbaren Genen führt . Mittlerweile befinden sich einige dieser PHD‐Inhibitoren in teils fortgeschrittenen Stadien klinischer Studien; die Wirksamkeit von Roxadustat zur Behandlung der Anämie konnte in diesem Jahr bestätigt werden …”

Section: Therapeutische Relevanz Und Eine Zweite Hif‐hydroxylaseunclassified

“…[27] Mittlerweile befinden sich einige dieser PHD-Inhibitoren in teils fortgeschrittenen Stadien klinischer Studien; die Wirksamkeit von Roxadustat zur Behandlung der Anämie konnte in diesem Jahr bestätigt werden. [28] Evolutionäre Analysen ergaben, dass das HIF-System nur in Tieren existiert, jedoch unabhängig von deren Komplexität: Selbst die einfachsten Vertreter, ohne Organe oder organisierte innere Strukturen, verfügen über eine funktionale HIF/PHD/pVHL-Kaskade. [29] Dies lässt den Schluss zu, dass das HIF-System offenbar zunächst auf zellulärer Ebene die Sauerstoffregulation modulierte.…”

Section: Der Sauerstoffsensor Der Menschlichen Zellenunclassified

Ein Gespür für Sauerstoff: Entdeckung des molekularen Mechanismus der zellulären Sauerstoffregulation rückt die Hydroxylierung von Makromolekülen in den Blickpunkt

Loenarz

2020

Angewandte Chemie

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Der diesjährige Nobelpreis für Physiologie oder Medizin wird drei Forschern verliehen, die ihre Karriere der Beantwortung einer grundlegenden wissenschaftlichen Fragestellung gewidmet haben: Wie wird in tierischen Zellen eine unzureichende Sauerstoffversorgung signalisiert, und mittels welcher Mechanismen passen sich Zellen auf derart geänderte Bedingungen an? Mit der Identifizierung des Hypoxie‐induzierten Faktors (HIF) und der Aufklärung assoziierter Signalwege bieten sich neue Forschungsansätze zur Therapie von Krebs, Anämie, und verschiedenen kardiovaskulären Erkrankungen. Der ausgeklügelte molekulare Mechanismus des zellulären Sauerstoffsensors führte zu breitem Interesse an der Familie der Eisen(II)/2‐Oxoglutarat‐abhängigen Enzyme – zuvor primär im Kontext komplexer Naturstoffbiosynthese bekannt. Neben substantiellem Fortschritt im Verständnis der Hydroxylierung biologischer Makromoleküle ermöglicht das Werk der diesjährigen Preisträger die Beschreitung neuer Wege für molekulare Wissenschaftler auf vielfältigen Gebieten wie C‐H‐Aktivierung, PROTAC‐Technologie, medizinische Chemie und Epigenetik.

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Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis

Cited by 461 publications

References 31 publications

End of an era for erythropoiesis‐stimulating agents in oncology

End of an era for erythropoiesis‐stimulating agents in oncology

An Oxygen Sensation: Progress in Macromolecule Hydroxylation Triggered by the Elucidation of Cellular Oxygen Sensing

Ein Gespür für Sauerstoff: Entdeckung des molekularen Mechanismus der zellulären Sauerstoffregulation rückt die Hydroxylierung von Makromolekülen in den Blickpunkt

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