Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia

Abstract

Background: Anemia is a common complication of chronic kidney disease. The hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) is a new class of oral drugs for the treatment of renal anemia. Summary: Clinical trials have consistently shown that HIF-PHIs can effectively increase hemoglobin in both the dialysis population and the non-dialysis population. The effects of HIF-PHIs in treating renal anemia include promoting endogenous erythropoietin production and facilitating iron mobilization. Several studies suggest that the erythropoiesis effect of roxadustat is less affected by inflammation. Careful monitoring of thromboembolic events and tumor before and during HIF-PHIs treatment is necessary. Key messages: HIF-PHIs are effective in correcting renal anemia. The long-term safety of HIF-PHIs needs to be further studied.

Evaluation of the Carcinogenic Potential of Enarodustat (JTZ-951), a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor, in 26-Week Tg.rasH2 Mouse Study and 2-Year Sprague-Dawley Rat Study

“…Several HIF-PH inhibitors have been approved and widely used for improvement of renal anemia. 3,5 Of the carcinogenicity evaluation of other HIF-PH inhibitors, those for roxadustat, daprodustat, and vadadustat have been already published. [14][15][16] The absence of carcinogenic potential in the present studies of enarodustat is in agreement with the results of the carcinogenicity studies of these other HIF-PH inhibitors.…”

“…The mechanism of action of HIF-PH inhibitors may raise theoretical safety concerns about tumorigenesis. 25 It is well documented that certain gene expressions induced by HIF activation lead to tumor formation and progression. 25 HIF-α has a potential to increase the expression of vascular endothelial growth factor (VEGF), a vascular endothelial cell-specific factor that increases vascular permeability and induces angiogenesis.…”

“…25 It is well documented that certain gene expressions induced by HIF activation lead to tumor formation and progression. 25 HIF-α has a potential to increase the expression of vascular endothelial growth factor (VEGF), a vascular endothelial cell-specific factor that increases vascular permeability and induces angiogenesis. 26,27 HIF-PH inhibitors may increase these risks through their effects on VEGF expression and increased VEGF levels in cells and/or tissues and this could possibly be a contributing factor to develop vascular tumors including hemangiosarcoma.…”

“…HIF-PH inhibitors mimic physiological responses to hypoxia, stabilizing HIF by regulating its degradation and leading to the expression of HIF-target genes involved in EPO production and iron metabolism. 3,4 At least 6 HIF-PH inhibitors have been developed: roxadustat, daprodustat, vadadustat, enarodustat, molidustat, and desidustat, all of which competitively inhibit binding of 2-oxoglutarate, an essential co-substrate of the HIF-PH enzymes. 5 Enarodustat (JTZ-951, CAS No.…”

HIF-Stabilisatoren: aktueller Stellenwert bei der Therapie der renalen Anämie

“…So war in der Studie DOLOMITES der Bedarf für eine parenterale Eisentherapie nur halb so hoch wie in der ESA-Vergleichsstudie [21]. Die verbesserte Eisenutilisation erklärt sich durch eine Herunterregulation von Hepcidin, dem Schlüsselenzym des Eisenstoffwechsels [26]. Auch bei den anderen HIF-Stabilisatoren war eine Tendenz zu einer reduzierten Eisensubstitution erkennbar, die zumindest aber bei den Daprodustat-Studien nicht signifikant war.…”