Part 2：Burden Of Anemia in Chronic Kidney Disease: Beyond Erythropoietin
Mar 17, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
HIF-PH Inhibitors in Development
Several other HIF-PH inhibitors are in development, with data available for solid-state (BAY 85-3934), enarodustat (JTZ-951), and desidustat (Zyan1) (Table 2). These studies show dose-dependent Hb increases and maintenance of Hb (in NDD-CKD) and maintenance of Hb (in DD- CKD) for solid-state [109], enarodustat [111, 112], and desidustat [113]. However, high Hb or a rapid rate of increase led to high incidences of early discontinuation from some studies of molidustat [109]. In the long-term extension studies DIALOGUE 3 and DIALOGUE
5, Hb was maintained in the target range (10–12 g/dl) for up to 36 months with molidustat, with a similar effect to darbepoetin or epoetin [110]. Increased TIBC and/or decreased hepcidin and/or ferritin were observed with these agents, which were generally well tolerated [109, 112, 113]. Furthermore, animal studies have indicated that prolonged exposure to roxadustat is not associated with prooncogenic activity [131, 132]. However, long-term clinical data are needed to confirm the safety of HIF-PH inhibitors regarding cardiovascular events and carcinogenesis.
Potential for Clinical Use of HIF-PH
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Inhibitors
HIF-PH inhibitors may present several practical advantages for patients with anemia of CKD. In addition to their oral route of administration, HIF-PH inhibitors may provide closer to physiologic EPO levels than the intermittent high levels attained with ESA therapy [87, 95]. Beyond erythropoiesis stimulation, HIF-PH inhibitors may improve iron homeostasis [133] and therefore reduce patients’ iron supplementation needs, thus potentially reducing costs and medication burden. Although data on the cost-effectiveness of HIF-PH inhibitors are limited, a meta-analysis was conducted to evaluate the cost-effectiveness of roxadustat in Chinese patients with NDD-CKD confirmed that roxadustat was cost-effective compared with placebo [134].
Evidence suggests that HIF-PH inhibitors may be efficacious without increasing inflammatory status [88], which could benefit patients with inflammation, associated with diabetic and non-diabetic kidney disease as well as those with acute inflammation (e.g., associated with infection). Although clinical data in patients who are ESA hyporesponsive are limited, key studies included patients with moderate inflammation, which is associated with reduced responsiveness to ESA therapy [135]. In the Chinese phase, 3 study of roxadustat in patients with DD-CKD, similar increases in Hb levels were observed in patients with normal and elevated C-reactive protein levels (B 4 and [4 mg/l) [35]. In addition, preliminary phase 3 data showed greater mean changes in Hb in patients with elevated high-sensitivity C-reactive protein levels receiving roxadustat versus epoetin alfa (DD-CKD) [91] or placebo (NDD-CKD) [98]. In these patients with moderate inflammation, who are potentially hyporesponsive to ESA therapy, HIF-PH inhibitors may be an effective alternative that avoids the need for high-dose ESA therapy. Further studies are needed to confirm the efficacy of HIF-PH inhibitors in patients who are ESA hyporesponsive. Finally, HIF-PH inhibitors may confer a reduced risk of cardiovascular events compared with ESAs in incident dialysis patients as a preliminary phase 3 pooled analysis showed a lower risk of MACE and MACE? with roxadustat versus epoetin alfa [130]. Further studies are needed to confirm the practical benefits of HIF-PH inhibitors in patients with anemia of CKD.
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Because HIF transcription factors regulate many biologic processes, there was concern that HIF-PH inhibitors may adversely affect cholesterol metabolism [136]. Based on animal studies, constitutive HIF-2 activation may theoretically suppress hepatic fatty acid b-oxidation and lipid synthesis and increase lipid storage capacity [136]. However, clinical studies showed reductions in total and low-density lipoprotein cholesterol (LDL-C) with roxadustat over 19–24 weeks [87, 94] and daprodustat over 24 weeks [103] as well as no changes in serum lipids with vadadustat over 16 or 20 weeks [106, 107] and only small changes in LDL-C with molidustat over 16 weeks [109]. Roxadus- tat phase 3 data showed decreases in low-density lipoprotein cholesterol versus placebo (NDD-CKD patients) [96] or versus ESA (DD- CKD patients) [35]. One potential mechanism for this reduction in serum cholesterol with roxadustat is thought to be a HIF-dependent decrease in 3-hydroxy-3-methylglutaryl coen- zyme A reductase levels, a rate-limiting enzyme in the cholesterol biosynthesis pathway [137].
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At-Home Anemia Management
At-home care of CKD is one of the goals outlined in the recent Executive Order, Advancing American Kidney Health, which aims to improve the diagnosis and treatment of CKD [138]. Compared with conventional hemodialysis, at-home hemodialysis benefits include reductions in LV mass and hypertension and increased HR-QOL, although there are no observed differences in anemia management [139, 140].
Because they are orally administered, HIF-PH inhibitors may confer advantages for at-home CKD care. In ESRD patients receiving peritoneal dialysis, the more common modality for at-home dialysis, roxadustat increased Hb to within the target range [141], and daprodustat pharmacokinetics were similar in patients receiving peritoneal dialysis or in-center hemodialysis, while Hb was maintained in those receiving peritoneal dialysis [142].
CONCLUSIONS
Anemia of CKD represents a considerable burden to both patients and the healthcare system. Although effective, the current standard of care is associated with inherent practical difficulties and safety concerns, including the increased risk of cardiovascular events and mortality. HIF- PH inhibitors may offer advantages over ESAs through more physiologic and effective means of treating anemia of CKD.
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ACKNOWLEDGEMENTS
Funding. This review, the Rapid Service, and Open Access Fees were funded by AstraZeneca.
Editorial Assistance. Sarah Greig, Ph.D. (Auckland, NZ), and Meri D. Pozo, Ph.D., CMPP (New York, NY, USA), of inScience Communications, Springer Healthcare provided editorial support, which was funded by AstraZeneca.
Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions. All authors wrote the first draft of the manuscript and participated in subsequent drafts, approved the submission of the manuscript, and are fully accountable for all aspects of the work.
Disclosures. Ramy M. Hanna and Elani Streja have nothing to disclose. Kamyar Kalan- tar-Zadeh reports personal fees from Abbott, AbbVie, Alexion, AMAG Pharma, Amgen, AstraZeneca, AVEO, Baxter, Chugai, Fresenius Medical Services, Genentech, Haymarket, Hospira, Fresenius Kabi USA, Keryx, Novartis, PCORI, Pfizer, Relypsa, Resverlogix, Sandoz, Sanofi, Shire, Vifor, UpToDate, and grants and personal fees from National Institutes of Health. None of the authors received honoraria for this work.
Compliance with Ethics Guidelines. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Open Access. This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any noncommercial use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third-party material in this article are included in the article’s Creative Commons license unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by- nc/4.0/.
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