SBIR-STTR Award

Direct to Phase II

Stroke affects more than 795,000 patients per year in the US and kills approximately 40,000. Long-term medical care expense for stroke in the US, costs over $34B per year. Large vessel occlusion (LVO) stroke accounts for almost 40% of ischemic strokes but causes 95% of mortality and 62% of long-term dependence. Mechanical thrombectomy (MT), or a combination of MT and tPA, has emerged as standard of care treatment of LVO stroke. Up to 60% of thrombectomy patients are first evaluated at spoke hospitals and transferred to hub hospitals for MT. `Time is brain' following stroke, the sooner therapy can be instituted, the greater the likelihood of preserving neurological function. A therapy that could be rapidly deployed in all stroke patients to preserve the brain could provide enormous potential benefit to stroke patients. NanO2TM (aka dodecafluoropentane emulsion, DDFPe) significantly decreased stroke volume (SV), by about 85%, and improved neurological assessment score (NAS) in rabbits when administered IV up to 3 hours following stroke and also improved SV and NAS in permanent rat MCAo. In a randomized, placebo-controlled Phase Ib/II clinical trial of acute ischemic stroke, in which patients receive standard reperfusion therapy, NanO2 was safe at all dose levels. The higher doses of NanO2 caused significantly better modified Rankin Scale (mRS) at 30 and 90-days post stroke. Early administration of NanO2 (<5 hours from onset) presented with significantly better NIH Stroke Scale (NIHSS) scores. NanO2 is active at very low doses (e.g. 0.1 to 0.17 mL of 2% w/vol emulsion per kg body weight) and clears via exhalation with a terminal half-life of about 90 minutes in humans. NanO2 was previously tested as an ultrasound contrast agent in 2,230 patients and was considered safe and approvable by the FDA and EMEA. The Specific Aims are 1) to manufacture DDFPe GMP for SPAN studies and to scale-up GMP manufacturing, 2) to test drug in tMCAo models in lean, adult and aged Wistar rats and 3) to perform studies in obese, diabetic Zucker rats and spontaneously hypertensive rats. Expected Outcome: NanO2 will show great efficacy in rodent tMCAo models enabling this drug to be considered as a candidate for entry into clinical trials in ischemic stroke sponsored by StrokeNet.

Public Health Relevance Statement:
NARRATIVE Stroke affects more than 795,000 Americans each year, kills approximately 140,000 and costs the US $34B peryear; large vessel occlusion (LVO) strokes account for almost 40% of ischemic strokes but cause 95% of mortalities and 62% of long-term dependence. Mechanicalthrombectomy (MT) has emerged as standard of care treatment for LVO stroke but MT is only available at specialized hospitals. DDFPe decreases stroke damage by about 85%, with potential to improve outcomes in stroke patients allowing time for treatment with MT. SPAN is a new program that will test promising agents to improve outcomes in stroke; we propose that SPAN test DDFPe. Terms: <21+ years old; Adult Human; adulthood; Adult; Affect; Anesthesia; Anesthesia procedures; Animals; Autopsy; necropsy; postmortem; Behavior; Body Weight; Brain; Brain Nervous System; Encephalon; Clinical Trials; comorbidity; co-morbid; co-morbidity; Contrast Media; Contrast Agent; Contrast Drugs; Radiopaque Media; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Eligibility Determination; Eligibility; Protocol Screening; Emulsions; Experimental Designs; Female; Half-Life; Hospitals; Human; Modern Man; Ischemia; Magnetic Resonance Imaging; MR Imaging; MR Tomography; MRI; MRIs; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Zeugmatography; male; mortality; United States National Institutes of Health; NIH; National Institutes of Health; Nervous System Physiology; Neurologic function; Neurological function; nervous system function; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Obesity; adiposity; corpulence; Oxygen; O element; O2 element; Patients; Placebos; Sham Treatment; sham therapy; Alteplase; Recombinant Tissue Plasminogen Activator; T-Plasminogen Activator; Tissue Activator D-44; Tissue Plasminogen Activator; Tissue-Type Plasminogen Activator; t-PA; Production; Oryctolagus cuniculus; Domestic Rabbit; Rabbits; Rabbits Mammals; Inbred SHR Rats; SHR Rats; Spontaneously Hypertensive Rats; spontaneous hypertensive rat; Wistar Rats; Zucker Rats; Rattus; Common Rat Strains; Rat; Rats Mammals; Reperfusion Therapy; reperfusion; Risk; Rodent; Rodentia; Rodents Mammals; Stroke; Apoplexy; Brain Vascular Accident; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; brain attack; cerebral vascular accident; cerebrovascular accident; stroked; strokes; Stroke Volume; Survival Analysis; Survival Analyses; Testing; Thinness; Leanness; Time; Tissue Preservation; Measures; Blinded; Caring; Thrombectomy; injuries; Injury; improved; Procedures; Acute; Specified; Specific qualifier value; Phase; Medical; Neurological; Neurologic; normotensive; Blood flow; diabetic; Measurement; Funding; programs; Mechanics; mechanic; mechanical; perfluoropentane; dodecafluoropentane; Hour; Dependence; Exhalation; Exhaling; Respiratory Expiration; Protocols documentation; Protocol; Route; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; meetings; meeting; American; cohort; Middle Cerebral Artery Occlusion; Modeling; anaerobic glycolysis; tissue oxygenation; tissue oxygen saturation; Ischemic Stroke; Dose; Tissue Viability; Data; Applications Grants; Grant Proposals; Randomized; randomisation; randomization; randomly assigned; Filament; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; nano; Placebo Control; placebo controlled; pre-clinical; preclinical; after stroke; poststroke; post stroke; cost; functional outcomes; Outcome; scale up; aged; Rat model of diabetes; diabetic rat model; diabetic rat; drug detection; drug testing; standard of care; commercial scale manufacturing; manufacturing ramp-up; scale up batch; scale up production; upscale manufacturing; manufacturing scale-up; phase 2 trial; phase II trial; improved outcome; experiment; experimental research; experiments; experimental study; preservation; stroke patient; stroke model; Phase 1b/2 Clinical Trial; Phase 1b/II Clinical Trial; Phase Ib/II Clinical Trial; Phase 1b/2 Trial; Phase Ib/II Trial; hypertensive; ultrasound; manufacture