The oral ferroportin inhibitor vamifeport improves hemodynamics in a mouse model of sickle cell disease

Abstract

Sickle cell disease (SCD) is an inherited hemolytic anemia caused by a single point mutation in the beta‑globin gene of hemoglobin that leads to synthesis of sickle hemoglobin (HbS) in red blood cells (RBCs). HbS polymerizes in hypoxic conditions, leading to intravascular hemolysis, release of free hemoglobin and heme, and increased adhesion of blood cells to endothelial vasculature, which causes painful vaso-occlusion and organ damage. HbS polymerization kinetics are strongly dependent on the intracellular HbS concentration; a relatively small reduction in cellular HbS concentration may prevent HbS polymerization and its sequelae. We hypothesized that iron restriction via blocking ferroportin, the unique iron transporter in mammals, might reduce HbS concentration in RBCs, thereby decreasing hemolysis, improving blood flow, and preventing vaso-occlusive events. Indeed, vamifeport (also known as VIT-2763), a clinical-stage oral ferroportin inhibitor, reduced hemolysis markers in the Townes model of SCD. The RBC indices of vamifeport-treated male and female Townes (HbSS) mice showed changes attributable to iron-restricted erythropoiesis: decreased corpuscular hemoglobin concentration mean and mean corpuscular volume, as well as increased hypochromic and microcytic RBC fractions. Furthermore, vamifeport reduced plasma soluble vascular cell adhesion molecule-1 concentrations, which suggests lowered vascular inflammation. Accordingly, intravital video microscopy of fluorescently labeled blood cells in the microvasculature of Townes mice treated with vamifeport demonstrated diminished adhesion to the endothelium and improved hemodynamics. These preclinical data provide a strong proof-of-concept for vamifeport in the Townes model of SCD and support further development of this compound as a potential novel therapy in SCD.

Structures of ferroportin in complex with its specific inhibitor vamifeport

“…Owing to the central role of hepcidin in regulating iron homeostasis, compounds that either mimic or block its function are of high therapeutic interest, and several agents are currently in clinical development for the treatment of anemia or iron overload conditions in different disorders ( Casu et al, 2018 ; Crielaard et al, 2017 ; Katsarou and Pantopoulos, 2018 ). Among those agents, the first orally available FPN inhibitor vamifeport (VIT-2763) is now in clinical trials for the treatment of β-thalassemia and sickle cell disease ( Manolova et al, 2019 ; Nyffenegger et al, 2022 ). On the molecular level, vamifeport was shown to compete with hepcidin for FPN binding with an IC 50 value in the low nanomolar range ( Manolova et al, 2019 ).…”

Structures of ferroportin in complex with its specific inhibitor vamifeport

“…Here, we have investigated the interaction between human ferroportin (hsFPN) and its inhibitor vamifeport, which was shown to ameliorate anemia and iron homeostasis in a mouse model of β-thalassemia and is now in clinical development for this disorder and sickle cell disease (Manolova et al, 2019; Nyffenegger et al, 2022). Our study has provided two major novel results, it has revealed the conformational changes that lead to the transition of FPN from the familiar outward-facing into an occluded state, where the access to the substrate binding site is blocked from both sides of the membrane (Figure 3), and it has defined the binding site of vamifeport in the same occluded conformation (Figure 4).…”

“…Owing to the central role of hepcidin in regulating iron homeostasis, compounds that either mimic or block its function are of high therapeutic interest and several agents are currently in clinical development for the treatment of anemia or iron overload conditions in different disorders (Casu, Nemeth, & Rivella, 2018; Crielaard et al, 2017; Katsarou & Pantopoulos, 2018). Among those agents, the first orally available FPN inhibitor vamifeport (VIT-2763) is now in clinical trials for the treatment of β-thalassemia and sickle cell disease (Manolova et al, 2019; Nyffenegger et al, 2022). On the molecular level, vamifeport was shown to compete with hepcidin for FPN binding with an IC 50 value in the low nanomolar range.…”

Iron is a modifier of the phenotypes of JAK2-mutant myeloproliferative neoplasms

“…Vamifeport (CSL Vifor) in 0.5% methylcellulose (Sigma Aldrich) was gavaged twice a day at 100 mg/kg. 32 PR73 was dissolved in SL220 (NOF Corp.) and injected intraperitoneally (i.p.) at 10 mg/kg twice per week.…”