JT Pharmaceuticals, Inc. — Department of Health and Human Services STTR Phase II: 101

Description

DESCRIPTION provided by applicant Stroke is a leading cause of human death and disability in the United States while clinical therapy for acute stroke is limited and unsatisfactoy The many failures in clinical trials strongly endorse the idea that to battle this multifaceted bran disorder novel strategies that target multiple cell types and different mechanisms are needed to achieve therapeutic effects in humans Among a few potential treatments of this approach hypothermia has shown remarkable neuroprotective up to effects against brain ischemia in animal and human studies Unfortunately available physical cooling techniques are ineffectual and often impractical Thus pharmacological compounds that can be utilized for hypothermia therapy have long been sought for the treatment of stroke It is expected that using pharmacologically induced hypothermia PIH the treatment can be initiated much earlier while even a small oC decrease in body temperature during early hours after stroke should prevent detrimental post stroke hyperthermia A mild to moderate hypothermia oC reduction will delay the evolution of ischemic injury and may extend the therapeutic window for other interventions such as the only FDA approved thrombolytic treatment using recombinant tissue plasminogen activator tPA In our Phase I investigation we demonstrated hypothermic effects of several novel neurotensin receptor NTR compounds and their marked neuroprotective effects against brain damage induced by ischemic stroke hemorrhage stroke and traumatic brain injury TBI in mouse and rat models We have identified two leading compounds for moving to the proposed Phase II investigation Our pilot study has also demonstrated the hypothermic effect of the leading compounds in non human primates In the Phase II study Specific Aim will test our hypothesis that the PIH therapy as a possible on site acute treatment is not only neuroprotective but also can prolong the therapeutic window of tPA treatment We will investigate this possibility in an embolic stroke model of mice that mimics clinical situations Specific Aim will identify possible side effects and toxicity of our compouns in order to confirm their suitability for further preclinical and clinical development and complete experiments necessary for IND preparation Specific Aim will examine the hypothermic effect of the selected NTR derivatives in monkeys to understand the dose response relationship and determine the duration and rewarming kinetics of their hypothermic effects MRI imaging in monkeys will provide valuable data for the drug effect on brain temperature cerebral blood flow the blood brain barrier gray and white matter changes and hemorrhage transformation after PIH It is expected that or more leading compounds will be validated for a future study in stroke monkey models and clinical trials in humans The translational research is pursued by a group of scientists with complementary expertise in basic and pre clinical stroke fields and will provide compelling evidence for a potential breakthrough in clinical stroke therapy PUBLIC HEALTH RELEVANCE Stroke is the third leading cause of human death and disability in the US To develop a clinically effective and feasible hypothermia therapy our Phase I study has synthesized and identified novel leading neurotensin receptor I derivatives for a novel pharmacological hypothermia therapy for ischemic and hemorrhage stroke This Phase II proposal is to improve the therapeutic window of tPA using pharmacological hypothermia and to evaluate the hypothermic effect in non human primate for clinical translation