Iron Regulation by Molidustat, a Daily Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, in Patients with Chronic Kidney Disease

Abstract

<b><i>Background/Aims:</i></b> The current treatment for anemia associated with chronic kidney disease (CKD) includes the administration of erythropoiesis stimulating agents (ESAs) combined with iron supplementation. Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has potential to treat anemia associated with CKD through increased erythropoietin production and improved iron availability. Here, we report the effect of molidustat on iron metabolism. <b><i>Method:</i></b> Parameters of iron metabolism were monitored in three 16-week, randomized, controlled, phase 2 studies assessing the safety and efficacy of molidustat in the treatment of anemia associated with CKD in different populations: treatment-naïve and previously ESA-treated patients not on dialysis, and previously ESA-treated patients on hemodialysis. Iron supplementation was left at the discretion of the investigator. <b><i>Results:</i></b> In treatment-naïve patients not on dialysis, transferrin saturation (TSAT), hepcidin, ferritin, and iron concentrations decreased with molidustat, whereas total iron binding capacity (TIBC) increased. Similar results were observed in previously ESA-treated patients not on dialysis, although changes in those parameters were larger in treatment-naïve than in previously ESA-treated patients. In previously ESA-treated patients receiving hemodialysis, hepcidin concentration and TIBC remained stable with molidustat, whereas TSAT and ferritin and iron concentrations increased. Generally, similar trends were observed in secondary analyses of subgroups of patients not receiving iron supplementation. <b><i>Conclusions:</i></b> Molidustat is a potential alternative to standard treatment of anemia associated with CKD, with a different mechanism of action. In patients not receiving dialysis, molidustat increases iron availability. In patients receiving hemodialysis, further investigation is required to understand fully the mechanisms underlying iron mobilization associated with molidustat.

The Influence of Inflammation on Anemia in CKD Patients

“…A single-center, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation 1 phase study demonstrated that oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO and that all doses of molidustat were well tolerated [124]. In three randomized, controlled, phase 2 studies, which are the part of the DIALOGUE (DaIly orAL treatment increasing endOGenoUs Erythropoietin) program, molidustat diminished transferrin saturation (TSAT), hepcidin, ferritin, and iron concentrations and increased total iron-binding capacity (TIBC) in treatment-naïve patients not on dialysis [125]. In these studies, the efficacy, safety, and tolerability of molidustat were compared with placebo or alternative ESA therapy in patients with anemia of CKD.…”

Anemia of Inflammation with An Emphasis on Chronic Kidney Disease

“…Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Another novel hypoxia-inducible factor prolyl hydroxylase inhibitor, Molidustat, has the potential to treat anemia of CKD by increasing erythropoietin production and improving iron availability particularly, in non-dialysis patients [141]. However, HIFs have roles in other biological pathways, including in the expression of vascular endothelial growth factor (VEGF), which is associated with retinal disease and cancer [142].…”

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in Patients with Renal Anemia: A Meta-Analysis of Randomized Trials

“…Group 1 (G1) included patients who went ≥12 weeks without receiving rhEPO, while group 2 (G2) included patients with stable ESA treatment for ≥8 weeks. DIALOGUE studies on molidustat, conducted by Akizawa et al [17, 18], included 3 trials of 3 kinds of people and 2 extensive trials. DIALOGUE 1 (D1) included patients with nondialysis-dependent chronic kidney disease (NDD-CKD) who were not previously treated with ESAs.…”