Novel von willebrand factor targeting thrombolytic TGD001 is safe and well tolerated in a phase 1 first-in-human trial

Abstract Introduction TGD001 is a novel thrombolytic fusion protein that binds with high affinity to von Willebrand factor (VWF) for targeted plasminogen activation. TGD001 is comprised of an antibody fragment that binds to VWF, fused with the catalytic domain of human urokinase-type plasminogen activator (UPA). Upon binding to VWF, the catalytic UPA domain in TGD001 is brought near plasminogen, resulting in activation to plasmin and initiation of thrombolysis at the thrombus. In contrast to standard-of-care (SoC) fibrin-targeting thrombolytics, TGD001's thrombolytic activity utilises the ubiquitous presence of VWF in all thrombi, resulting in thrombolysis independent of fibrin content, positioning TGD001 as a universal thrombolytic. TGD001's in vivo thrombolytic potential was demonstrated in animal models of thrombotic thrombocytopenic purpura (TTP) and acute ischemic stroke. In these models, TGD001 effectively degraded thrombi of varying compositions via targeted destruction of platelet-VWF complexes by plasmin, in both the macro- and microvasculature, resulting in improved outcomes. Immune-mediated TTP (iTTP) is a thrombotic microangiopathy (TMA) hallmarked by severely deficient ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity and the formation of widespread VWF and platelet-rich thrombi in the microvasculature. The current SoC treatments aim to inhibit thrombus formation, eliminate disease triggers, and restore ADAMTS13 activity. However, the initial thrombus burden at the time of diagnosis (i.e. acute TTP episode) remains unresolved, leading to prolonged ischemic organ damage, potentially contributing to long-term sequelae and disabilities. In an upcoming Phase 1/2 study, the authors aim to address the initial thrombus burden with a novel thrombolytic approach, and to demonstrate the safety of TGD001 in the treatment of iTTP/TMA, while also focusing on its potential to reduce ischemic tissue damage and improve clinical outcomes. The presented Phase 1 healthy volunteer data provide the foundation for the planned iTTP/TMA clinical trial. Methods In a first-in-human, randomized, double-blind, placebo-controlled single-ascending dose study, the safety, tolerability, and pharmacokinetics (PK) of intravenously administered TGD001 were assessed in 34 healthy adult male participants across four dose cohorts. Participants were randomized to TGD001 or placebo, respectively, in a 3:2 (Cohort 1, n=10) or 3:1 (Cohort 2 – 4, n=8 per cohort) ratio. TGD001 or placebo was administered as a 1-hour intravenous (IV) administration in the first five participants and as a 1-minute controlled rapid IV administration in subsequent participants. Study assessments included adverse events (AEs), clinical laboratory tests, PK, pharmacodynamic biomarkers, rotational thromboelastometry, and a skin bleeding test. Data are reported as of 23 July 2025, after the last follow-up visit. Results Single IV administrations of TGD001 were well tolerated in healthy participants. Sixteen AEs were reported (headache, n=1; injection site hematoma, n=5; injection site hemorrhage, n=2; rhinitis, n=1; gastroenteritis, n=1; nasopharyngitis, n=3; middle ear inflammation, n=1; dental procedure, n=1; wrist fracture, n=1), of which six (grade 1 injection site hematoma, n=4; grade 2 injection site hemorrhage, n=2) were deemed related to the IMP (TGD001 or placebo). No other systemic bleedings occurred. No cohort- or study-stopping criteria were met. All TEAEs were transient, reversible and consistent with TGD001's mechanism of action. The TGD001 PK profile appears dose-proportional in terms of Cmax. Tmax was within 15 minutes after the end of the infusion. The clearance and half-life (t1/2) presented with variability between individuals. Individual calculated t1/2 values ranged from 1.8 to 8.1 hours. Dose-dependent trends were observed in key pharmacodynamic biomarkers, including plasminogen, fibrinogen, and alpha2-antiplasmin. All skin bleeding test results were in the normal range. Conclusion TGD001 was well-tolerated in healthy participants, and the observed pharmacological profile supports the hypothesis of rapid thrombolysis in patients with iTTP and other TMAs. This effect may contribute to a reduction of ischemic thrombus burden and improved clinical outcomes. These findings support the initiation of an upcoming Phase 1/2 trial in iTTP and selected TMAs, as well as further development in acute ischemic stroke.