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 erythropoiesisFigure 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

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