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

Restriction of iron availability by ferroportin inhibition is a novel approach to treating non‐transfusion‐dependent thalassemia (β‐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.