Interest of HIF stabilizers in home dialysis

Abstract

Hypoxia-inducible factor (HIF) stabilizers or dustats are orally administered small molecules with very low renal elimination (without adaptation during chronic kidney disease (CKD) analogues with antagonistic effect of 2-oxoglutarate, a naturally occurring substrate of HIF-Prolyl Hydroxylase at the origin of the inhibition of this enzyme. This results in a simulated state of hypoxia allowing the accumulation of HIF-α in the cells followed by coordinated erythropoiesis with erythropoietin synthesis, decreased hepatic hepcidin production and optimization of iron metabolism. HIF stabilizers have only been studied in non-inferiority clinical trials versus erythropoiesis stimulating agents (ESAs). The primary endpoint for the therapeutic trials of all these different molecules was the change in hemoglobin level. Dustat corrects anemia in advanced non-dialysis and dialysis CKD in a similar way to ESAs.
Six HIF stabilizers molecules are in advanced development: Roxadustat, Daprodustat, Vadadustat, Enarodustat, Desidustat and Molidustat. Only Roxadustat or Evrenzo®, currently has a marketing authorization in Europe obtained in August 2021. Only two studies have been dedicated to peritoneal dialysis, one with Roxadustat, the other with Daprodustat. Home dialysis appears to be an elective indication for HIF stabilizers because of their absence of cold chain necessity and their positive impact on iron metabolism and the difficulties and imperfections of the current treatment of anemia with ESA and intravenous iron in this patient population.

1. Reminder on erythropoiesis stimulating agents

Recombinant erythropoietin (EPO), introduced in 1987, represented a therapeutic revolution in the management of anemia in chronic kidney disease (CKD), transforming the quality of life of dialysis patients and improving the mortality and morbidity associated with this severe anemia . It is a pathophysiological treatment because the anemia in CKD is mainly related to a significant decrease in erythropoietin production by the diseased kidneys, as evinced by the sharply decreased levels of circulating erythropoietin during CKD; moreover, there is a parallel between the severity of renal failure and the decrease in circulating erythropoietin levels(Panjeta et al., 2017). Erythropoietin is a growth factor acting on the bone marrow, which is necessary for the early stages of erythropoiesis; EPO thus acts on burst-forming unit-erythroid cells (BFU-E cells), colony-forming unit-erythroid cells (CFU-E cells) and proerythroblasts (Besarab et al., 2009) via a specific receptor. It should be noted that in addition to this early EPO-dependent phase, erythropoiesis has a later phase dependent on the incorporation of iron into the heme nucleus of hemoglobin (Figure 1).

Figure 1.EPO and iron in erythropoiesis Figure according to Besarab’s article,(Besarab et al., 2009).

In addition to its primary action on erythropoiesis, EPO is also a pleiotropic growth factor acting during fetal development, not only on erythropoiesis but also on angiogenesis, fetal brain development, and also neuronal, retinal and vascular protection, and wound healing in adulthood (Vaziri & Ateshkadi, 1999). EPO production takes place in the liver during fetal life and in the kidneys from birth. It has recently been shown that during CKD, the liver takes over from the deficient kidneys in the synthesis of erythropoietin, especially as renal function is impaired(Seigneux S et al., 2016).

2. Erythropoietin synthesis is stimulated by hypoxia and HIF

EPO production occurs in the kidney (and liver) in response to changes in tissue oxygenation or hypoxia(Koury & Haase, 2015) [6]. Hypoxia leads to transcription of the erythropoietin gene in peritubular interstitial fibroblasts and in the liver(Seigneux S et al., 2016) [6]. EPO promotes erythropoiesis in pluripotent bone marrow cells committed to the erythroblastic lineage (BFU-E and CFU-E) and proerythroblasts [6]. The resulting increase in circulating erythrocytes and hemoglobin leads to improved tissue oxygenation [6]. The hypoxia inducible factor (HIF) transcription factor in EPO-producing kidney cells regulates erythropoietin production in a hypoxia-inducible manner (Figure 2)(Koury & Haase, 2015).

Figure 2.Synthesis of EPO. Figure adapted from: 1. Koury MJ and Haase VH, (Koury & Haase, 2015), 2. Locatelli F, et al,(Locatelli et al., 2017-01-25) .

The level of HIF-α is regulated by specific enzymes called HIF-prolyl hydroxylase (HIF-PHD) that trigger its degradation at the proteasome. There are three HIF-PHD enzymes in humans that hydroxylate HIF-α and thus regulate its stability: HIF-PHD1, HIF-PHD2, and HIF-PHD3. The enzyme HIF-PHD2 is considered the primary regulator of HIF under normal oxygenation conditions (Locatelli et al., 2017-01-25).

The activation of HIF is a physiological response of the body in the presence of low oxygen levels (hypoxia). Indeed, at normal oxygen levels, HIF-prolyl hydroxylase remains abundant. It causes the degradation of HIF-α and thus prevents the activation of a hypoxic response. In contrast, during periods of hypoxia (low oxygen), HIF-prolyl hydroxylase is inactive, because oxygen is required for the enzymatic reaction, and HIF-α will therefore accumulate. HIF-α then dimerizes with constitutively expressed HIF-β, and the dimer moves to the nucleus, allowing transcription of key genes that manage hypoxia(Locatelli et al., 2017-01-25). Several hundred genes are direct targets of HIF; these genes play a role in cell migration, cell growth and cycle, angiogenesis, vasomotor regulation, glucose metabolism and availability, and barrier functions, as well as EPO synthesis and iron availability for erythropoiesis (Figure 3)(Schödel & Ratcliffe, 2019).

Figure 3. HIF activation . Figure adapted from Locatelli F, et al,(Locatelli et al., 2017-01-25) [7].

3. General information on HIF stabilizers or Dustats

3.1 The different molecules

While there are about a dozen molecules in development, only six are at an advanced stage.

The first molecule in this new class is Roxadustat or Evrenzo®, developed by the American biotechnology company Fibrogen (San Francisco, USA) and produced by Astellas Pharma (Tokyo, Japan) in Japan, Asia and Europe and by AstraZeneca (Cambridge, UK) in North America. Evrenzo® obtained European marketing authorization (AMM) in August 2021(Source Title, n.d.).

The second molecule in the dustat class is Daprodustat, developed by the British laboratory GlaxoSmithKline (GSK, Brentford, UK) which just obtained AMM in the USA in February 2023 (Food & Administration, n.d.). The four other molecules currently in advanced development are Vadadustat (Vafseo®) from Akebia Therapeutics (Cambridge, Massachusetts, USA) and Otsuka Pharmaceutical (Chiyoda, Tokyo, Japan)); Enarodustat (Enaroy® from Kyowa Hakko Kirin, Tokyo, Japan); Desidustat (Oxemia® from Zydus Cadila Healthcare, Ahmedabad, India); and, finally, Molidustat from Bayer (Leverkusen, Germany) (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022).

3.2 Commonalities in the development and clinical trials of HIF stabilizers

These are orally administered molecules (as opposed to the intravenous and subcutaneous routes for ESAs) which have only been the subject of non-inferiority clinical studies compared with first-generation ESAs (Eprex®, Neorecormon®) and second-generation ESAs (Aranesp®)(Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022) .

The primary endpoint for the therapeutic trials of all these different molecules was the change in hemoglobin level (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022); only the studies of Daprodustat used a primary endpoint combining hemoglobin level and major adverse cardiac events (MACE), including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022). These clinical trials were conducted in both hemodialysis patients and patients with advanced non-dialysis CKD; there were very few studies involving peritoneal dialysis (PD) patients, and none involving home hemodialysis patients, daily or otherwise (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022). The duration of these studies varied from 6 months to 1 year. There was no significant pharmacovigilance signal; a common point of these molecules is their important pharmaceutical potency, which is superior to that of ESAs and often produces rapid corrections of hemoglobin, which may explain the excess of cases of fistula thrombosis as well as the rare phlebitis and pulmonary embolisms observed during these studies (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022) .

4. Mechanisms of action of HIF stabilizers or Dustats

These are small synthetic molecules with very low renal elimination (without dosage adjustment during CKD). They are analogs with an antagonistic effect on 2-oxoglutarate, a natural substrate of HIF-prolyl hydroxylase at the origin of the inhibition of this enzyme. This results in a simulated state of hypoxia, allowing the accumulation of HIF-α in the cells (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022).

Pharmacological inhibition of HIF-prolyl hydroxylase 2 induces transcription of EPO genes and inhibition of hepcidin synthesis, resulting in efficient and coordinated erythropoiesis. The production of erythrocytes follows the conjunction of EPO production and the synthesis of its cellular receptors associated with an increase in iron availability. This optimization of martial metabolism is due to increased intestinal iron absorption and iron release by macrophages and cells of the reticuloendothelial system following the inhibition of hepcidin synthesis and the arrest of degradation of ferroportin, the protein exporting iron from these cells (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022). In an ancillary study of Roxadustat, it was shown that blood erythropoietin concentrations in patients treated with this dustat were close to physiological values, whereas circulating erythropoietin concentrations on Epoetin alfa appeared to be largely supra-physiological (by a factor of 5 to 6) Figure 4) (Provenzano et al., 2016). In the same study, Roxadustat significantly reduced hyperhepcidemia in dialysis patients and increased iron utilization for erythropoiesis, as evinced by the increase in the hemoglobin content of reticulocytes (CHr) (Figure 5) . It should be remembered that the inhibition of hepatic hepcidin under dustat is indirect, due to the medullary production of erythroferrone.

Figure 4.Figure 4. Pharmacodynamic effects of roxadustat compared to epoetin alfa. Figure according to Provenzano R, et al,(Provenzano et al., 2016) [13].

Figure 5.Pharmacodynamic effects of roxadustat compared to epoetin alfa. Figure according to Provenzano R, et al,(Provenzano et al., 2016) [13].

5. Roxadustat or Evrenzo®

Evrenzo® is the first dustat marketed in Europe. Its clinical development included trials involving 9,600 patients either in advanced renal failure or on dialysis (Figure 6)(Tang et al., 2021) . It has similar efficacy to ESAs in treating CKD anemia (Figure 7) (Tang et al., 2021). The European Medicines Agency’s (EMA) summary of product characteristics states (verbatim), «What is it used for? Evrenzo is a medicine used in adults to treat the symptoms of anemia caused by chronic renal failure. How is Evrenzo used? Patients treated with an ESA and whose haemoglobin levels are stable should not be switched to Evrenzo unless there is clinical justification and expected benefits.»

Figure 6.Roxadustat clinical trial overviewFigure adapted from: 1. Shutov E, et al. Nephrol Dial Transplant. 2021;36:1629-1639 ; 2. Fishbane S, et al. J Am Soc Nephrol. 2021;32(3):737–755; 3. Coyne DW, et al. Kidney Int Rep. 2020;6(3):624–635; 4. Barratt J, et al. Nephrol Dial Transplant. 2021; 36 : 1616-1628 ; 5. Provenzano R, et al. Nephrol Dial Transplant. 2021;36:1717-1730; 6. Csiky B, et al. Adv Ther 2021;38 : 5361-5380 ; 7. Fishbane S, et al. J Am Soc Nephrol 2022; 33: 850–866 ; 8. Charytan C, et al. Kidney Int Rep. 2021;6(7):1829–1839.

Figure 7.Studies Pyrenees, Rockies, Sierras about Roxadustat Figure from Epar-evrenzo® [15].Average hemoglobin level (g/dL) over time to 52 weeks.

In other words, according to the summary of product characteristics established by the EMA, Evrenzo® can be given in the first intention in pre-dialysis and dialysis in ESA-naive patients and in the second intention in pre-dialysis and dialysis in case of resistance or intolerance to ESAs (Source Title, n.d.).

The opinion of the Transparency Commission of the French National Authority for Health (HAS) for Evrenzo® dated March 30, 2022 specifies that its (verbatim) «medical service rendered (MSR) is important only in patients not already treated with an erythropoiesis-stimulating agent, not dialyzed or dialyzed for less than 4 months» Table I.[(Source Title, n.d.). Evrenzo® has a level V medical benefit (ISMR V) (Table II.) (Source Title, n.d.).

Currently, Roxadustat is also marketed in other European Union countries and in the United Kingdom in the European AMM indication, as well as in Japan and China in a broader indication (non-dialyzed and dialyzed CKD).

Table I.Medical service rendered (MSR) according to the HAS

Table II. Improvement of the medical service rendered (IMSR) according to the HAS

6. Daprodustat

The clinical development of Daprodustat included 8,169 patients either in advanced renal failure or on dialysis (Figure 8)(Fu et al., 2022) . It has similar efficacy to ESAs in treating anemia in CKD (Fu et al., 2022). The decision of the EMA regarding the European AMM of Daprodustat is expected in April or May 2023, and should logically lead to the submission of a reimbursement application to the HAS Transparency Commission (CT) in the fall of 2023. The opinion of the CT should be known at the beginning of 2024, and the marketing of Daprodustat should occur during 2024 after the price has been fixed by the Economic Committee for Health Products.

Figure 8.ASCEND clinical programs for Daprodustat Figure adapted by GSK: 1. Singh AK, et al. Presented at American Society of Nephrology - Kidney Week 2021:FR-OR66. 2. Singh AK, et al. JAMA Intern Med. 2022;182(6):592-602. 3. Coyne DW, et al. Presented at American Society of Nephrology - Kidney Week 2021:PO0487. 4. Johansen KL, et al. Presented at American Society of Nephrology - Kidney Week 2021:FR-OR53.

7. Vadadustat

Vadadustat (Vafseo® from Akebia Therapeutics (Cambridge, Massachusetts, USA) and Otsuka Pharmaceutical (Chiyoda, Tokyo, Japan)) received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in February 2023, which is a key step in obtaining a European AMM (Source Title, n.d.). Its clinical development has included 8,438 patients on dialysis or with advanced non-dialysis CKD, and it has similar efficacy to ESAs in treating anemia due to renal failure (Xiong et al., 2022).

8. HIF Stabilizers and Home Dialysis

Despite the real interest in this new therapeutic class in home dialysis, linked to the absence of the cold chain, which is complex to implement in this situation, and to the positive modulation effect of dustats on martial metabolism, which is strongly disrupted in dialyzed CKD, there is a paucity of data. Studies are limited to 2 works on peritoneal dialysis (PD), one involving Roxadustat, the other involving Vadadustat(Akizawa et al., 2019-07-31)(Dasgupta et al., 2022-11) .

The first study was of Roxadustat and involved 56 Japanese patients treated with PD; 13 were ESA-naive and 43 on ESA then converted to this dustat. The follow-up was 24 weeks. Both types of patients were within the 10-12 g/dl target by week 6 and remained within the target during the 24 weeks of the study (Figure 9)(Akizawa et al., 2019-07-31).

The second work dedicated to PD was a pre-specified analysis of the ASCEND-D study (NCT02879305) of Daprodustat in dialysis, which included 340 PD patients randomized (1/1)to either Daprodustat or Darbepoetin alfa. This study, presented at the last American Society of Nephrology (ASN) congress, showed an identical cardiovascular safety and efficacy profile on anemia between Darbepoetin and Daprodustat in PD (Figure 10) (Dasgupta et al., 2022-11).

Figure 9. Study of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with anemiaFigure according to Akizawa T, et al, (Akizawa et al., 2019-07-31).

Figure 10. Efficacy of Daprodustat in peritoneal dialysis: a pre-specified analysis of the ASCEND-D studyFigure according to Dasgupta I, et al,(Dasgupta et al., 2022-11)

9. What positioning of HIF stabilizers for nephrologists?

In recent years, the nephrological community had shown an interest and enthusiasm for the new therapeutic class of dustats (Koury & Haase, 2015)(Locatelli et al., 2017-01-25)(Schödel & Ratcliffe, 2019). However, this has greatly diminished in the last 3 years due to the unfinished nature of the studies on the different molecules, which have been limited to non-inferiority studies. There have not been any superiority studies or specific studies on patients who are hypo-responders or resistant to ESAs, a medical problem that is currently unresolved and is a source of great concern to the nephrologists (Babitt et al., 2021) . Only home dialysis has escaped this negative judgment regarding HIF stabilizers and appeared for Locatelli and Del Veccio, in their recent narrative review published in the Journal of the American Society of Nephrology (JASN) in late 2022, as an elective indication for this new class. This has been due to the HIF stabilizers’ lack of need for the cold chain, their positive impact on martial metabolism, and their oral mode of administration, which have been compared with the difficulties and imperfections of the current treatment of anemia with ESAs and iron derivatives in this patient population (Locatelli & Del Vecchio, 2022).

10. Conclusions

HIF stabilizers are a new and very promising therapeutic class for anemia in advanced or end-stage renal disease. They seem to be of great interest in home dialysis because of their oral form, the absence of the cold chain and their positive effect on martial metabolism.

Links of interest

Dr. Guy Rostoker reports consulting fees from Astellas (consulting on Roxadustat, 2019-2021, 2023), GlaxoSmithKline (consulting on Daprodustat, 2022-2023), Vifor (consulting on Kapruvia, 2021-2023).

He reports research funding from Amgen, Astellas, Baxter, Hemotech, Gambro Hospal, Nipro, Physidia and Theradial. He also declares speaking fees from Amgen, Aguettant, Astellas, Roche, Sanofi and Vifor.

References

1. Eschbach J.W., Egrie J.C., Downing M.R., Browne J.K., Adamson J.W.. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987; 316(2):73-78. DOI
2. Panjeta M., Tahirović I., Sofić E., Ćorić J., Dervišević A.. Interpretation of erythropoietin and haemoglobin levels in patients with various stages of chronic kidney disease. J Med Biochem. 2017; 36(2):145-152. DOI
3. Besarab A., Hörl W.H., Silverberg D.. Iron metabolism, iron deficiency, thrombocytosis, and the cardiorenal anemia syndrome. Oncologist. 2009; 14(Suppl 1):22-23. DOI
4. Vaziri N.D., Ateshkadi A.. Effects of epoetin on vascular biology. Nephrol Dial Transplant. 1999; 14(suppl 2):46-49. DOI
5. Seigneux SAK Meinild Lundby, L Berchtold, AH Berg, P Saudan, C Lundby. Increased synthesis of liver erythropoietin with CKD. J Am Soc Nephrol. 2016; 27(8):2265-2269. DOI
6. Koury M.J., Haase V.H.. Anaemia in kidney disease: harnessing hypoxia responses for therapy. Nat Rev Nephrol. 2015; 11(7):394-410. DOI
7. Locatelli F., Fishbane S., Block G.A., Macdougall I.C.. Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients. Am J Nephrol. 2017; 2017;45(3):187-199DOI
8. Schödel J., Ratcliffe P.J.. Mechanisms of hypoxia signalling: new implications for nephrology. Nat Rev Nephrol. 2019; 15(10):641-659. DOI
9. European Public Assessment Report (EPAR) EMA Evrenzo.Publisher Full Text | DOI
10. Food U.S., Administration Drug. FDA approval Daprodustat.Publisher Full Text | DOI
11. Vareesangthip K., Satirapoj B., Noppakun K.. The Role of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors for anemia in chronic kidney disease: a narrative review. Int J Nephrol Renovasc Dis. 2023.
12. Locatelli F., Del Vecchio L.. Hypoxia-Inducible Factor–Prolyl Hydroxyl Domain Inhibitors: From Theoretical Superiority to Clinical Noninferiority Compared with Current ESAs?. J Am Soc Nephrol. 2022; 33(11):1966-1979. DOI
13. Provenzano R., Besarab A., Wright S., Al Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study. Am J Kidney Dis. 2016; 67(6):912-924. DOI
14. Tang M., Zhu C., Yan T., Zhou Y., Lv Q., Chuan J.. Safe and Effective Treatment for Anemic Patients with Chronic Kidney Disease. An Updated Systematic Review and Meta-Analysis on Roxadustat. Front. Pharmacol. 2021; 12(658079)DOI
15. Publisher Full Text
16. Publisher Full Text
17. Fu Z., Geng X., Chi K., Al Efficacy and safety of Daprodustat versus rhEPO for anemia in patients with chronic kidney disease: a meta-Analysis and trial sequential analysis. Front Pharmacol. 2022; 13(746265)DOI
18. Committee for Medicinal Products for human Use (CHMP) positive opinion for Vadadustat.Publisher Full Text | DOI
19. Xiong L., Zhang H., Guo Y., Song Y., Tao Y.. Efficacy and safety of Vadadustat for anemia in patients with chronic kidney disease: a systematic review and meta-analysis. Front Pharmacol. 2022; 12(795214)DOI
20. Akizawa T., Otsuka T., Reusch M., Ueno M.. Intermittent oral dosing of Roxadustat in peritoneal dialysis chronic kidney disease patients with anemia: a randomized, phase 3, multicenter, open-label study. Ther Apher Dial. 2019; 2020;24(2):115-125DOI
21. Dasgupta I., Mallett S.A., Bhatt P.R., Al Efficacy and cardiovascular safety of Daprodustat for the management of renal anemia in peritoneal dialysis patients: a pre-specified analysis of the ASCEND-D Trial. Poster. 2022; TH-PO688Publisher Full Text
22. Babitt J.L., Eisenga M.F., Haase V.H., Al Controversies in optimal anemia management: conclusions from a kidney disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2021; 99(6):1280-1295. DOI