THE FERROPORTIN INHIBITOR CPD-348 AMELIORATES THALASSEMIA SYMPTOMS IN HBB(TH3/+) MICE

Hepcidin mimetics have been developed to improve anemia by mitigating ineffective erythropoiesis, reducing iron overload by limiting iron absorption and diminishing transfusion burden/iron overload. Previous studies have shown that hepcidin mimetics ameliorated disease symptoms in the Hbb^th3/+ model of β-thalassemia by increasing hemoglobin levels and reducing reticulocyte counts, whereas iron chelators alone did not have the same effects. In this present study we tested the novel oral small molecule hepcidin mimetic Compound 348 (Cpd-348) in comparison to vamifeport, and in presence or absence of the iron chelator deferasirox in thalassemia mice.

Mice were dosed once daily for 7 weeks with Cpd-348 (2, 8, 30, or 120 mg/kg PO), vamifeport (30, or 120 mg/kg PO), or vehicle control. In a subsequent study, thalassemia mice were dosed with Cpd-348 (30 mg/kg PO) or vehicle, in presence or absence of deferasirox. Our results demonstrated that Cpd-348 alone or in presence of deferasirox ameliorated β-thalassemia symptoms in mice: Cpd-348 treatment at lower dose than vamifeport increased hemoglobin >1 g/dL, reduced reticulocytes, improved red blood cell (RBC) half-life, increased mature CD71^- cells, reduced spleen weight (possibly by reducing extramedullary hematopoiesis), and improved RBC health by reducing ROS and mitochondrial content. In contrast, deferasirox alone did not have the benefits described for Cpd-348, although, as expected, effectively reduced liver iron content.

In summary, Cpd-348 treatment ameliorated disease symptoms in β-thalassemia mice in absence or presence of the iron chelator deferasirox. Cpd-348 may be beneficial for the treatment of β-thalassemia and other hepcidin-related disorders.