Abstract Body: Introduction: Plasminogen activators (Alteplase and Tenecteplase) for acute ischemic stroke (AIS), while effective, suffer from limitations and untoward effects. These include a narrow therapeutic window, suboptimal thrombolysis of larger clots, paradoxical microthrombosis, neurotoxic effects and hemorrhage from the supratherapeutic doses needed to overcome effects of alpha-2 antiplasmin. TS23, an alpha-2 antiplasmin antibody, offers a novel paradigm shift in thrombolysis. It works by “releasing the brakes” on the body’s natural ability to lyse thrombi (Figure 1); preclinical data suggest a greater efficacy, longer therapeutic window and improved safety compared to plasminogen activators.

Methods: SISTER (NCT05948566) is an ongoing, Phase 2, prospective, randomized, placebo-controlled, blinded, adaptive dose-finding clinical trial that aims to identify a dose of TS23 that is safe and potentially more efficacious than placebo. We will enroll 300 AIS patients at up to 50 sites. Patients with baseline NIHSS ≥6, who can receive study drug within 4.5-24 hours of last known well, and with evidence of core-penumbra mismatch on baseline perfusion imaging, but not planned to receive standard of care acute stroke reperfusion therapies (endovascular treatment and/or thrombolysis), will be eligible. The primary safety and efficacy outcomes are any intracranial hemorrhage and NIH Stroke Scale Score (adjusted for the baseline in analysis) at 30 (±6) h, and these will be analyzed using a novel utility approach to maximize efficient detection of the most promising TS23 dose(s).

Results: First participant was enrolled in May 2025. Currently, 35 sites are active. There have been no significant safety concerns identified thus far.

Conclusions: SISTER will rigorously test the safety and preliminary efficacy of TS23 among patients with AIS within 4.5-24 hours of last known well. If the trial is successful, pivotal testing of TS23 for AIS will be planned.