SBIR-STTR Award

Seventeen million people each year suffer from an ischemic stroke and millions are left dead and disabled. Treatment with recombinant tissue plasminogen activator (r-tPA) is only modestly effective at reducing disability and it is associated with brain hemorrhage in up to 30% of patients when serial imaging studies are performed. Brain hemorrhage causes death and disability and, is the major cause of early mortality in r-tPA treated patients; there is no proven effective therapy. Stentriever therapy improves reperfusion in ischemic stroke, but it is only available for a minority of patients and it carries a comparable risk of intracranial hemorrhage. A safe treatment for ischemic stroke, used alone or 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 convert a lead, high-affinity, ultra-specific matrix metalloproteinase-9 inhibitor (MMP-9i) into an optimal therapy for stroke. MMP-9 is a protease induced by ischemia or r-tPA therapy, which degrades the extracellular and the neurovascular matrix. MMP-9 is induced by brain ischemia and by r-tPA therapy; there is abundant evidence that MMP-9 contributes to ischemic brain injury including bleeding during ischemic stroke. Pre-clinical proof-of-concept data, from multiple laboratories, in a number of species and models, shows that inhibiting the action of MMP-9, significantly reduces ischemic brain infarction and disability. Experimental evidence shows that when the lead MMP-9i is added to r-tPA therapy it markedly reduces brain hemorrhage, infarction, swelling, neurobehavioral disability and death in experimental ischemic stroke. Due to its exquisite potency and specificity, this MMP-9i has extraordinary therapeutic potential for reducing morbidity and mortality—without causing the serious adverse events associated with broad spectrum MMP inhibitors. The goal of this Phase I proposal is to follow FDA guidance to convert this potent, specific lead MMP-9i into a humanized, first-in-class therapy for ischemic stroke.

Public Health Relevance Statement:
Current therapy for ischemic stroke only benefits a minority of patients because it causes serious complications such as bleeding. We are developing an ultra-specific, high potency therapeutic agent that, in experimental studies, significantly reduces bleeding and mortality when given with current stroke treatment. This new agent has the potential to significantly improve outcomes for patients with ischemic stroke.

Project Terms:
Acute; Address; Affinity; Alteplase; antibody engineering; antibody inhibitor; Binding; Biological Response Modifier Therapy; Brain Edema; Brain hemorrhage; Brain Infarction; Brain Ischemia; Catalytic Domain; Cause of Death; Cessation of life; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; cross reactivity; Data; Development; disability; Disabled Persons; Disease; drug candidate; Early treatment; Edema; effective therapy; Enzymatic Biochemistry; enzyme activity; Enzymes; Evaluation; Experimental Models; experimental study; extracellular; FDA approved; Gelatinase B; Gelatinases; Goals; Health Care Costs; Hemorrhage; Human; humanized antibody; imaging study; improved; improved outcome; in vivo Model; Infarction; inhibitor/antagonist; innovation; Intracranial Hemorrhages; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Laboratories; Lead; Left; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Minority; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; mortality; Mus; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; neurobehavioral; Neurological outcome; neurovascular; New Agents; novel therapeutics; optimal treatments; Parents; Patient-Focused Outcomes; Patients; Peptide Hydrolases; pharmacokinetics and pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; phase I trial; post stroke; pre-clinical; Pre-Clinical Model; preclinical development; preclinical study; Preparation; prevent; Production; Reperfusion Therapy; Reporting; Risk; Role; Safety; serial imaging; Serious Adverse Event; side effect; Small Business Innovation Research Grant; Specificity; stroke risk; stroke therapy; Swelling; Talents; Techniques; Therapeutic; Therapeutic Agents; Thromboembolism; Tissues; Translational Research; Venous; Work

Each year ~12 million people each year suffer from an ischemic stroke. Millions are left disabled and ~3 milliondie. Treatment with recombinant tissue plasminogen activator (r-tPA) treatment significantly reduces patientdisability. However, r-tPA therapy does not reduce mortality and it causes some form of brain hemorrhage in upto 30% of patients. In selected r-tPA-treated patients with large vessel occlusions, endovascular thrombectomysignificantly 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 majorcause of early mortality in r-tPA-treated patients. A safer treatment for ischemic stroke, used in combination withthese 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 selectivelytarget matrix metalloproteinase-9 (MMP-9) in the vascular compartment. Levels of MMP-9 rise acutely in thevascular compartment of the brain in response to ischemia and r-tPA therapy. MMP-9 is a protease that degradesthe neurovascular matrix and contributes to ischemic brain injury and hemorrhage. Small molecule, broadspectrum MMP inhibitors block MMP-9 activity, but these agents may cross the blood brain barrier and inhibitboth harmful and protective metalloproteinases, which appears to contribute to their failure in clinical trials. Toaddress these limitations, Translational Sciences, Inc. developed a high-affinity, ultra-specific MMP-9 inhibitorthat selectively targets MMP-9 in the vascular compartment. When this lead monoclonal antibody inhibitor wasadded 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, wesuccessfully 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 furtherdevelop this novel therapeutic for the treatment of ischemic stroke, by completing key milestones such as mastercell bank creation, bioreactor production, release testing and pivotal safety-toxicology studies in preparation foran IND.

Public Health Relevance Statement:
Our best medical therapy for ischemic stroke helps many patients, but it also may cause serious or fatal brain bleeding. We and others have shown that MMP-9 contributes to brain hemorrhage and ischemic brain injury during stroke. Our studies demonstrate that a specific MMP-9 inhibitor reduces bleeding and mortality in experimental ischemic stroke and we seek to develop this MMP-9 inhibitor to improve stroke treatment.

Project Terms:
<92-kDa Gelatinase><92-kDa Type IV Collagenase>