The oral ferroportin inhibitor vamifeport prevents liver iron overload in a mouse model of hemochromatosis.

Hemochromatosis is an inherited iron overload condition caused by mutations that reduce the levels of the iron-regulatory hormone hepcidin or its binding to ferroportin. The hepcidin-ferroportin axis is pivotal to iron homeostasis, providing opportunities for therapeutic intervention in iron overload disorders like hemochromatosis. The aim of this study was to evaluate the efficacy of the oral ferroportin inhibitor vamifeport in the C282Y mouse model, which carries the most common mutation found in patients with hemochromatosis. A single oral dose of vamifeport lowered serum iron levels in C282Y mice, with delayed onset and shorter duration than observed in wild-type mice. Vamifeport induced transient hypoferremia by inhibiting ferroportin and resulted in a feedback regulation of liver in wild-type mice, which was absent in C282Y mice, reflecting the dysregulated systemic iron sensing in this hemochromatosis model. Chronic dosing with vamifeport led to sustained serum and liver iron reductions in C282Y mice, as well as markedly reducing liver expression in C282Y mice, suggesting distinct regulation of liver expression following acute or continuous iron restriction via vamifeport. At the tested dose, vamifeport retained its activity when combined with phlebotomy and did not significantly interfere with liver iron removal by phlebotomy in C282Y mice. These data demonstrate that chronic vamifeport treatment significantly reduces serum iron levels and prevents liver iron loading in the C282Y mouse model of hemochromatosis, thus providing preclinical proof of concept for the efficacy of vamifeport in hemochromatosis with or without phlebotomy.