S142 FIRST‐IN‐CLASS ORAL FERROPORTIN INHIBITOR: MODE OF ACTION AND EFFICACY IN A MOUSE MODEL OF BETA‐THALASSEMIA INTERMEDIA

Background: β‐thalassemia is a rare genetic disease in which ineffective erythropoiesis leads to anemia and iron overload. Currently, no efficacious oral medication with a good tolerability profile is available to patients with β‐thalassemia. Correction of unbalanced iron absorption by induction of hepcidin synthesis or supplementation of hepcidin mimetics has been shown to normalize the dysregulated iron metabolism in β‐thalassemia 1 . However, hepcidin modulation or replacement strategies all require parenteral drug administration. Restricting iron availability by VIT‐2763, the first‐in‐class clinical stage oral ferroportin (Fpn) inhibitor, ameliorated anemia and the dysregulated iron homeostasis in the Hbb th3/+ mouse model of β‐thalassemia intermedia 2 . Aims: To address the mode of action and preclinical efficacy of VIT‐2763 in a mouse model of β‐thalassemia intermedia. Methods: The potency of VIT‐2763 and hepcidin in an iron efflux assay was investigated using T47D cells which express endogenous human Fpn. Fpn internalization was studied using MDCK cells constitutively expressing human Fpn with a fluorescent tag. The efficacy of VIT‐2763 was studied in a mouse model of β‐thalassemia intermedia (Hbb th3/+ ). Results: The potency and mode of action of VIT‐2763 and hepcidin were compared in a set of cell‐based assays. Strikingly, VIT‐2763 (EC 50  = 68 ± 21 nM, mean ± standard deviation, n = 6) blocked iron efflux in cells with similar potency to hepcidin (EC 50  = 123 ± 46 nM mean ± standard deviation, n = 6), despite being structurally unrelated and more than five‐fold smaller in molecular weight than hepcidin. However, VIT‐2763 showed slower kinetics and triggered incomplete Fpn internalization and degradation compared to hepcidin. These data might indicate that VIT‐2763 directly and efficiently blocks Fpn‐mediated iron export in addition to Fpn internalization. A kinetic study in the Hbb th3/+ mouse model of β‐thalassemia intermedia revealed that VIT‐2763 dosed for one week significantly reduced hemichromes in red blood cells (RBCs), increased RBC counts and hemoglobin, thereby indicating rapid improvement of erythropoiesis. Over time, VIT‐2763 further ameliorated the RBC phenotype, such as decreased formation of reactive oxygen species, improved mitochondria clearance in mature RBCs and extended RBC life‐span. Moreover, VIT‐2763 corrected the elevated blood leukocyte counts in Hbb th3/+ mice, likely through effects on myeloid precursors in the spleen. A proof‐of concept clinical study with VIT‐2763 as a novel, first in‐class oral drug targeting Fpn for the treatment of β‐thalassemia is currently in the planning phase. Summary/Conclusion: Iron restriction by pharmacologically targeting the Fpn‐hepcidin axis with the first in‐class oral Fpn inhibitor VIT‐2763 provides a novel therapeutic opportunity in β‐thalassemia.