Dodecafluoropentane emulsion (DDFPe), NanO2™ as Cerebroprotectant in Ischemic Stroke

ABSTRACT / PROJECT SUMMARY 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.