Abstract Number: Esoc2026a1328 Tgd001, a Novel VWF-Targeting Thrombolytic, Effectively Degrades Ex-Vivo Human Stroke Thrombi and Demonstrates Safety and Activity in a Phase 1 Healthy Volunteer Trial

Abstract Background and aims Thrombus burden, composition and lysis resistance are major barriers to effective thrombolytic treatment in acute ischaemic stroke (AIS). TGD001, a von Willebrand factor (VWF)-targeting thrombolytic fusion protein, addresses composition and responsiveness to thrombolysis by degrading both VWF and fibrin via plasminogen activation. It outperforms tPA in AIS models with diverse thrombus compositions. Here, we confirm its novel MoA using ex-vivo thrombolysis experiments and translation of pharmacological activity in healthy volunteers. Methods Ex-vivo thrombolysis: Thrombi extracted from patients with AIS during mechanical thrombectomy were used for TGD001-mediated thrombolysis and histological assessments. Furthermore, TGD001, TGD001-NT (without VWF-targeting antibody), and tPA were assessed in rotational thromboelastometry (ROTEM) assays using healthy donor plasma. Clinical safety and pharmacology: TGD001 was administered to 34 healthy adult male participants across four dose cohorts (1-2 mg) in a randomized, double-blind, placebo-controlled single-ascending dose trial. Results TGD001 lysed ex-vivo human AIS thrombi, with no evidence of treatment resistance. Thrombus degradation increased with VWF content (r = 0.903;P 0.01). In ROTEM assays, TGD001, but not TGD001-NT or tPA, induced dose-dependent thrombolysis without impairing thrombus formation. One-minute TGD001 infusions across a pharmacologically active dose range were well-tolerated without dose or treatment-limiting events, spontaneous bleeding, or signs of immunogenicity. The half-life ranged from 2 to 8 hours. The thrombolytic MoA and activity were confirmed by dose-dependent plasminogen activation and increased D-dimer levels. Conclusions TGD001′s robust thrombolytic activity against treatment-resistant thrombi and favorable clinical safety profile support its advancement in the Phase 1b/2a AIS trial ongoing in Germany, Spain, Poland, and Serbia. Conflict of interest Mariëlle Klein Hesselink: Employed by TargED Biopharmaceuticals B.V.; Steven de Maat: Employed by TargED Biopharmaceuticals B.V. and owns equity in the company.; Sarah Mc Fie: Employed by TargED Biopharmaceuticals B.V.; Simon de Meyer: Received funding from KU Leuven, Fonds voor Wetenschappelijk Onderzoek Vlaanderen and TargED Biopharmaceuticals B.V. for this research.; Sarah Vandelanotte: Nothing to disclose; Olivier François: Nothing to disclose; H. Bart van der Worp: Received research funding from the Dutch Heart Foundation, ZonMw, and the European Union, and received fees for consultation from Boehringer Ingelheim and TargED Biopharmaceuticals B.V., all paid to his institution.; Joan Montaner: Received honoraria as a consultant from TargED Biopharmaceuticals B.V.; Götz Thomalla: Received honoraria as consultant or lecturer from Acandis, Astra Zeneca, Bayer, Boehringer Ingelheim, BristolMyersSquibb/Pfizer, Daiichi Sankyo, Lilly, and TargED.; Josefin-Beate Holz: Consultant for TargED Biopharmaceuticals B.V.