Ischemic stroke is the second leading cause of death and disability worldwide. Tissue plasminogen activator (TPA), the only approved treatment for ischemic stroke, dissolves the culprit fibrin thrombus to restore blood flow and relieve the brain from ischemia. Unfortunately, after prolonged ischemia, TPA restores full blood flow in only 30% of patients and may cause serious or fatal complications; this restricts TPA use to a minority of stroke patients. New insights into the molecular control of fibrin thrombus dissolution (fibrinolysis) assign a central role to alpha-2-antiplasmin (a2AP) in determining outcomes after ischemic stroke. High a2AP levels are linked to increased risk of ischemic stroke and of TPA failure. Pre-clinical studies have shown that a2AP markedly in- creases brain injury, in a dose-dependent fashion. Conversely, a2AP deficiency or monoclonal antibody inacti- vation of a2AP, profoundly reduces brain injury, apoptosis, hemorrhage, and swelling. Even after prolonged brain ischemia, a2AP inactivation reduces microvascular thrombosis and MMP-9 expression (a marker of acute inflammation). As a result, a2AP inactivation prevents death and disability after ischemic stroke. Thus, in pre-clinical studies, a2AP inactivation is safer, more effective and has a longer therapeutic window than TPA. Given the enormous treatment potential of this approach, we initiated the development of a novel therapeutic antibody for inactivating a2AP, with research support from NIH/NINDS. We have performed robust and rigorous pre-clinical studies and we have completed pivotal safety-toxicology studies showing safety and biomarker efficacy. In a Phase I trial in humans, a single bolus dose of the a2AP-inactivating antibody, induced dose-related neutralization of a2AP and endogenous fibrinolysis, as indicated by rising D-dimer levels. This a2AP inactivating antibody was well-tolerated and did not cause bleeding or serious adverse events. In partnership with key members of the StrokeNet team we are developing a Phase II trial of this a2AP inactivating antibody in ischemic stroke to examine safety, biomarker efficacy and proof of concept. To enable a Phase II trial, this proposal seeks needed funding to support cGMP biomanufacturing of this a2AP- inactivating antibody.
For millions of patients who suffer ischemic stroke there is no safe and effective therapy. To address this need, we have developed a first-in-class therapy that has been shown to be safe and to improve outcomes after experimental ischemic stroke.
