A first-in-human study assessing the safety, pharmacokinetics, and pharmacodynamics of TU7710, a recombinant factor VIIa-transferrin fusion protein, in warfarin-pretreated healthy male participants

초록

Background: Recombinant activated factor (F)VII (rFVIIa) is a key therapeutic agent for managing bleeding in patients with hemophilia and inhibitors, but its clinical use is limited by a short half-life requiring frequent dosing. TU7710 is a novel rFVIIa-transferrin fusion protein designed to extend circulation time by leveraging transferrin-mediated recycling via the transferrin receptor pathway. Objectives: This study investigated the safety, pharmacokinetics, and pharmacodynamics of single ascending-dose intravenous administration of TU7710, in warfarin-pretreated healthy male participants. Methods: In each cohort, 8 healthy male participants were randomized in a 6:2 ratio to receive either TU7710 or placebo. Participants underwent 8 days of warfarin pretreatment to achieve a stable prothrombin time (PT)/international normalized ratio (INR) of 2.00 to 3.00 prior to dosing. TU7710 or placebo was administered intravenously (100-1600 mu g/kg). Key pharmacokinetic and pharmacodynamic parameters, including FVIIa activity and PT/INR, as well as antidrug antibodies were assessed. Results: A total of 41 participants were enrolled, and 40 were included in the analyses. Administration of TU7710 resulted in an immediate increase in FVIIa activity (median Tmax, 0.25 hours), with a mean residence time ranging from 6.70 to 10.52 hours. Pharmacodynamic assessments showed a corresponding normalization of PT/INR in all participants treated with TU7710. Dose-dependent reductions in PT/INR were observed. TU7710 was well tolerated across all dose levels. Conclusion: TU7710 demonstrated an extended half-life and effectively normalized PT/INR levels in warfarin-pretreated healthy participants. These findings support further clinical development of TU7710 as a potential therapeutic option for patients with hemophilia.

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