Oral ferroportin inhibitor vamifeport for improving iron homeostasis and erythropoiesis in β-thalassemia: current evidence and future clinical development

Abstract

Introduction: In β-thalassemia, imbalanced globin synthesis causes reduced red blood cell survival and ineffective erythropoiesis. Suppressed hepcidin levels increase ferroportin-mediated iron transport in enterocytes, causing increased iron absorption and potentially iron overload. Low hepcidin also stimulates ferroportin-mediated iron release from macrophages, increasing transferrin saturation (TSAT), potentially forming non-transferrin-bound iron, which can be toxic. Modulating the hepcidinferroportin axis is an attractive strategy to improve ineffective erythropoiesis and limit the potential tissue damage resulting from iron overload. There are no oral β-thalassemia treatments that consistently ameliorate anemia and prevent iron overload. Areas covered: The preclinical and clinical development of vamifeport (VIT-2763), a novel ferroportin inhibitor, was reviewed. PubMed, EMBASE and ClinicalTrials.gov were searched using the search term 'VIT-2763ʹ. Expert opinion: Vamifeport is the first oral ferroportin inhibitor in clinical development. In healthy volunteers, vamifeport had comparable safety to placebo, was well tolerated and rapidly decreased iron levels and reduced TSAT, consistent with observations in preclinical models. Data from ongoing/ planned Phase II studies are critical to define its potential in β-thalassemia and other conditions associated with iron overabsorption and/or ineffective erythropoiesis. If vamifeport potentially increases hemoglobin and reduces iron-related parameters, it could be a suitable treatment for non-transfusiondependent and transfusion-dependent β-thalassemia.

Efficacy and Mechanism of Roxadustat plus Oral Iron in the Treatment of Elderly Chronic Kidney Disease with Anemia

“…These findings suggest that Roxadustat plus oral iron contributes to mitigate the anemia symptoms in elderly patients with CKD and anemia, and facilitate the metabolism. The results may attributed to the fact that Roxadustat can reduce the hepcidin of the patient's body, thereby increasing the TRF level of the patient's body and helping the patient to stabilize the body's Fe level [ 14 , 15 ]. Rubeor et al revealed that the level of inflammatory factors in patients with CKD and anemia may have a certain relationship with the disease, and over half of the patients are accompanied by active inflammatory response [ 16 , 17 ].…”

“…Oral iron is associated with adverse reactions such as gastrointestinal irritation. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor developed in recent years that can correct anemia via multiple pathways by inactivating prolyl hydroxylase Enzyme (PHD) under hypoxia, and regulating the main transcription factor of EPO gene; under normal circumstances, HIF- α and HIF- β that can be hydroxylated by PHD and degraded by the body bind to the nucleus and further bind to the hypoxia response element, thereby mediating gene transcription [ 14 ]. Hypoxia-inducible factor prolyl hydroxylase inhibitor induces functional HIF transcriptional response by stabilizing HIF and inhibiting PHD, and promotes the expression of erythropoietin receptor while promoting the production of endogenous EPO, thereby improving anemia.…”

TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis

“…Patients reported improved symptoms, and adverse events consisted mainly of nonserious injection site reactions. Vamifeport is an orally administered small molecule drug which binds to ferroportin, blocks cellular iron export, and causes ferroportin internalization [ 44 ]. Vamifeport induced iron restriction and ameliorated β-thalassemia in preclinical models [ 45 ].…”

Therapeutic perspective for children and young adults living with thalassemia and sickle cell disease

“…The trial has been completed in November 2021, but the results are yet to be published. A phase IIb trial including adults with TDT is being planned with the primary objective to evaluate the efficacy of several increasing doses of vamifeport as measured by reduction in RBC transfusion burden [ 36 ]. Other molecules with hepcidin-like action may reduce iron absorption and redistribution and improve erythropoiesis.…”