Preventing Neurovascular Matrix Degradation and Hemorrhage in Acute Ischemic Stroke

Each year ~12 million people each year suffer from an ischemic stroke. Millions are left disabled and ~3 million die. Treatment with recombinant tissue plasminogen activator (r-tPA) treatment significantly reduces patient disability. However, r-tPA therapy does not reduce mortality and it causes some form of brain hemorrhage in up to 30% of patients. In selected r-tPA-treated patients with large vessel occlusions, endovascular thrombectomy significantly improves reperfusion and outcome, but it also carries a comparable risk of intracranial hemorrhage. Unfortunately, there is no proven effective therapy for brain hemorrhage, which causes disability and is the major cause of early mortality in r-tPA-treated patients. A safer treatment for ischemic stroke, used in combination with these therapies, which reduces hemorrhage, as well as brain infarction and brain edema, could save lives, reduce patient disability and lower health care costs. To address this need, Translational Sciences, Inc. seeks to develop an ultra-specific therapeutic to selectively target matrix metalloproteinase-9 (MMP-9) in the vascular compartment. Levels of MMP-9 rise acutely in the vascular compartment of the brain in response to ischemia and r-tPA therapy. MMP-9 is a protease that degrades the neurovascular matrix and contributes to ischemic brain injury and hemorrhage. Small molecule, broad spectrum MMP inhibitors block MMP-9 activity, but these agents may cross the blood brain barrier and inhibit both harmful and protective metalloproteinases, which appears to contribute to their failure in clinical trials. To address these limitations, Translational Sciences, Inc. developed a high-affinity, ultra-specific MMP-9 inhibitor that selectively targets MMP-9 in the vascular compartment. When this lead monoclonal antibody inhibitor was added to r-tPA therapy, even after prolonged ischemia, it markedly reduced brain hemorrhage, infarction, swelling, neurobehavioral disability and death in experimental ischemic stroke. In Phase I of this project, we successfully converted this monoclonal antibody into a recombinant, first-in-class, therapeutic MMP-9 inhibitor. In this Phase II proposal, we will follow FDA guidance and specific pre-IND meeting recommendations, to further develop this novel therapeutic for the treatment of ischemic stroke, by completing key milestones such as master cell bank creation, bioreactor production, release testing and pivotal safety-toxicology studies in preparation for an IND.