167 Reversible VWF Inhibitor Lyses MCA Occlusion 6 Hours after Large Vessel Occlusion Stroke

Abstract

INTRODUCTION: Acute ischemic stroke (AIS) is the leading cause of combined morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) represents the only approved pharmacological treatment for AIS but is limited to treating those within 4.5 hours of stroke onset because of the risk of intracranial hemorrhage. Moreover, it is ineffective in treating large vessel occlusion (LVO) stroke. For this population, endovascular mechanical thrombectomy (MT) effectively recanalizes the occlusion but is limited to highly-specialized hospitals, leaving the vast majority without timely acute treatment. METHODS: Utilizing a canine embolic middle cerebral artery occlusion (eMCAO) model of LVO stroke, we assessed DTRI-031 on vessel recanalization after 6 hours of LVO stroke by digital subtraction angiography (DSA). We also measured the effect of recanalization on infarct volume (efficacy) and hemorrhage (safety) using magnetic resonance imaging (MRI). Finally, we assessed the ability of DTRI-025, an oligonucleotide that binds DTRI-031 to reverse DTRI-031 activity. RESULTS: DTRI-031 administration after 6 hours of LVO stroke resulted in >TICI 2A in 62.5% and >TICI 2B in 50% of canines (n = 8). Negative control group demonstrated no revascularization (n = 7). Recanalization resulted in reduced infarct volume compared to negative control (p < 0.05, unpaired t-test). None of the animals that received DTRI-031 had intracranial hemorrhage on MRI. Finally, DTRI-025 completely reversed the activity of DTRI-031 within 5 minutes of administration in both whole blood impedance aggregometry (WBA) and PFA-100. CONCLUSION: DTRI-031 effectively recanalizes LVO after 6 hours of stroke onset with reduced infarct volume and no incidence of hemorrhage. DTRI-025 rapidly reverses DTRI-031. This drug/reversal agent combination represents a robust yet safe approach to treat AIS.