Oral ferroportin inhibitor VIT-2763: First-in-human, phase 1 study in healthy volunteers.

ABSTRACT: Restriction of iron availability by ferroportin inhibition is a novel approach to treating non-transfusion-dependent thalassemia (?-thalassemia intermedia). This first-in-human, Phase I study (https://www.clinicaltrialsregister.eu; EudraCT no. 2017-003395-31) assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of single- and multiple-ascending doses (SAD and MAD) of the oral ferroportin inhibitor, VIT-2763, in healthy volunteers. Participants received VIT-2763 5/15/60/120/240?mg or placebo in the SAD phase and VIT-2763 60/120?mg once daily, VIT-2763 60/120?mg twice daily, or placebo for 7?days in the MAD phase. Seventy-two participants completed treatment. VIT-2763 was well tolerated and demonstrated a similar safety profile to the placebo. There were no serious or severe adverse events, or discontinuations due to adverse events. VIT-2763 absorption was relatively fast, with detectable levels 15 to 30?minutes post-dose. Following multiple dosing there was no apparent change in absorption and accumulation was minimal. Mean elimination half-life was 1.9 to 5.3 hours following single dosing, and 2.1 to 3.8 hours on Day 1 and 2.6 to 5.3 hours on Day 7, following repeated dosing. There was a temporary decrease in mean serum iron levels with VIT-2763 single doses ?60?mg and all multiple doses; mean calculated transferrin saturation (only assessed following multiple dosing) also temporarily decreased. A shift in mean serum hepcidin peaks followed administration of all iron-lowering doses of VIT-2763. This effect was less pronounced after 7?days of multiple dosing (aside from with 120?mg once daily). These results support the initiation of clinical studies in patients with non-transfusion-dependent thalassemia and documented iron overload due to ineffective erythropoiesis.

SUBMITTER: Richard F 

PROVIDER: S-EPMC6916274 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature