SBIR-STTR Award

Acute ischemic stroke (AIS) is the result of a blood clot in a cerebral artery. Currently, AIS remains a leading killer and the leading cause of long-term disability, which annually impacts nearly 700,000 Americans. Because brain tissue rapidly dies, time to reperfusion is critical in both preventing death and improving neurological outcomes. While economic burden associated with ischemic stroke are high in the United States (US), it is projected to increase from $72B in 2013 to $183B by 2030. Intravenous use of tissue plasminogen activator (tPA) is the standard of care for AIS, with thrombectomy recommended for proximal large vessel occlusion in the anterior circulation. This strategy results in improvements in long-term neurological outcomes over tPA alone. However, over half of thrombectomy-treated patients die or are left moderately-to-severely disabled, despite a majority achieving complete or partially- complete blood flow restoration. Inaccessible distal emboli post thrombectomy are a primary reason for poor outcomes, which result in incomplete flow in up to half of cases. Patients not achieving complete recanalization tend to be hospitalized longer, show weaker neurological improvements, have worse long-term neurological outcomes, and experience more hemorrhage, versus those with complete recanalization. No options currently exist for treating distal emboli given that current tools are too large and intra-arterial infusion of thrombolytic agents has shown limited-to-no success due to distal occlusions creating stagnant columns of blood proximal to the clot which restricts their diffusion to less than a few millimeters per hour. Pulse Therapeutics, Inc. (PTI) has made a breakthrough discovery using magnetic particles to adjunctively convey thrombolytic agents over 100X faster. In vitro and in vivo work confirm that this technology improves thrombolytic agent conveyance and clot lysis. It has also been shown that low doses of tenecteplase (TNK) are superior to tPA. This project?s aims are to develop the technology for an intra-arterial procedure in the treatment of AIS. For Phase I, benchtop, in vitro, and in vivo work will be conducted to demonstrate proof of concept and optimize TNK and particle dosing and therapy delivery. FDA feedback using Phase I results will be sought to improve Phase II aims. Phase II will assess the system?s impact on TNK pharmacokinetics and aggravation of hemorrhage. In addition, an angiography suite-compatible workstation will be developed and flow studies using neuro phantoms will be repeated under fluoroscopy to assess anticipated clinical workflow. Early FDA engagement indicates that the technology may be evaluated as a device given persuasive mode of action and biocompatibility preliminary studies. Importantly, the PTI technology supports the FDA?s mission to reinforce the value of comprehensive stroke centers and promises to improve care for the nearly 350,000 AIS victims showing visible clot in the anterior circulation. If successful, this technology would represent the first drug delivery nanotechnology approved as a medical device in the US.

Project Terms:
Acute; Alteplase; American; Angiography; Animal Model; Animals; Anterior; base; Biological; biomaterial compatibility; Blood; Blood Circulation; Blood coagulation; Blood flow; brain tissue; Caring; cerebral artery; Cessation of life; Clinical; Coagulation Process; commercialization; Cytolysis; Data; Development; Devices; Diffusion; digital; digital imaging; disability; Disabled Persons; Distal; Dose; Drug Delivery Systems; Drug Kinetics; Dyes; Economic Burden; Effectiveness; efficacy study; Embolism; Engineering; experience; Feasibility Studies; Feedback; Fibrin; Fibrinolytic Agents; Fluoroscopy; Goals; Half-Life; Hemorrhage; high resolution imaging; Hour; Image; improved; In Vitro; in vivo; Intra-Arterial Infusions; Intracranial Hemorrhages; Intravenous; Ischemic Stroke; Left; Magnetism; Medical Device; Methods; millimeter; minimally invasive; Mission; Modeling; Nanotechnology; Neurologic; Neurological outcome; new technology; Oryctolagus cuniculus; Outcome; particle; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiologic pulse; prevent; primary endpoint; Procedures; Reperfusion Therapy; Resolution; restoration; Risk; Rodent Model; Safety; safety study; safety testing; Site; Small Business Innovation Research Grant; standard of care; Stroke; stroke event; stroke victims; Study of magnetics; success; System; Technology; Tenecteplase; Therapeutic; Thrombectomy; thrombolysis; Time; tool; Uncertainty; United States; United States National Institutes of Health; Whole Blood; Work;

Acute ischemic stroke (AIS) is the result of a blood clot in a cerebral artery. Currently, AIS remains a leadingkiller and the leading cause of long-term disability, which annually impacts nearly 700,000 Americans. Becausebrain tissue rapidly dies, time to reperfusion is critical in both preventing death and improving neurologicaloutcomes. While economic burden associated with ischemic stroke are high in the United States (US), it isprojected to increase from $72B in 2013 to $183B by 2030. Intravenous use of tissue plasminogen activator (tPA) is the standard of care for AIS, with thrombectomyrecommended for proximal large vessel occlusion in the anterior circulation. This strategy results inimprovements in long-term neurological outcomes over tPA alone. However, over half of thrombectomy-treatedpatients die or are left moderately-to-severely disabled, despite a majority achieving complete or partially-complete blood flow restoration. Inaccessible distal emboli post thrombectomy are a primary reason for pooroutcomes, which result in incomplete flow in up to half of cases. Patients not achieving complete recanalizationtend to be hospitalized longer, show weaker neurological improvements, have worse long-term neurologicaloutcomes, and experience more hemorrhage, versus those with complete recanalization. No options currentlyexist for treating distal emboli given that current tools are too large and intra-arterial infusion of thrombolyticagents has shown limited-to-no success due to distal occlusions creating stagnant columns of blood proximalto the clot which restricts their diffusion to less than a few millimeters per hour. Pulse Therapeutics, Inc. (PTI) has made a breakthrough discovery using magnetic particles to adjunctivelyconvey thrombolytic agents over 100X faster. In vitro and in vivo work confirm that this technology improvesthrombolytic agent conveyance and clot lysis. It has also been shown that low doses of tenecteplase (TNK) aresuperior to tPA. This project's aims are to develop the technology for an intra-arterial procedure in thetreatment of AIS. For Phase I, benchtop, in vitro, and in vivo work will be conducted to demonstrate proof ofconcept and optimize TNK and particle dosing and therapy delivery. FDA feedback using Phase I results willbe sought to improve Phase II aims. Phase II will assess the system's impact on TNK pharmacokinetics andaggravation of hemorrhage. In addition, an angiography suite-compatible workstation will be developed andflow studies using neuro phantoms will be repeated under fluoroscopy to assess anticipated clinical workflow. Early FDA engagement indicates that the technology may be evaluated as a device given persuasivemode of action and biocompatibility preliminary studies. Importantly, the PTI technology supports the FDA'smission to reinforce the value of comprehensive stroke centers and promises to improve care for the nearly350,000 AIS victims showing visible clot in the anterior circulation. If successful, this technology wouldrepresent the first drug delivery nanotechnology approved as a medical device in the US.

Public Health Relevance Statement:
The goal of this SBIR FastTrack application is to provide a minimally-invasive tool to lyse otherwise untreatable emboli in acute ischemic stroke (AIS). Of the 700,000 AIS events in the US each year, nearly half are associated with a large vessel occlusion which, when a thrombectomy is performed, can create untreatable distal emboli (up to half of cases) that result in poorer neurological outcomes. By leveraging Pulse Therapeutics' breakthrough discovery in which magnetics are used to intra-arterially and adjunctively convey tenecteplase over 100X faster for lysing otherwise impossible-to-treat emboli in the distal vasculature, a transformational and much-needed tool can be provided which promises to improve neurological outcomes for currently untreatable AIS victims.

Project Terms: