Novel anti-neuroinflammatory drug for aneurysmal subarachnoid hemorrhage (aSAH)

治疗动脉瘤性蛛网膜下腔出血（aSAH）的新型抗神经炎症药物

基本信息

批准号：
10481419
负责人：
Victor Shifrin
金额：
$ 49.84万
依托单位：
IMMUNOCHEM THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10481419
关键词：
Acute Address Alzheimer&apos s Disease Amendment Aneurysm Aneurysmal Subarachnoid Hemorrhages Animal Model Anti-Inflammatory Agents Arterial Disorder Attenuated Brain Caring Cerebral Ischemia Cerebral hemisphere hemorrhage Cerebrovascular Spasm Chemicals Chronic Chronic Brain Injury Clinical Clinical Research Clinical Trials Contracts Cyclic GMP Dangerousness Data Diagnosis Disabled Persons Disease Disease Progression Documentation Dose Drug Exposure Drug Interactions Drug Kinetics Drug Targeting Endothelin-1 Enteral Exhibits FDA approved Fatality rate Frequencies Functional disorder Funding Future Healthcare Hemolysis Hospitals Human Impaired cognition Independent Living Inflammation Inflammatory Response Injury Intervention Intravenous Left Life Magnesium Sulfate Medical Modeling Molecular Morbidity - disease rate Motor Nerve Degeneration Nervous System Physiology Nervous System Trauma Neurocognitive Neuroglia Neurologic Neurological Models Neurological outcome Neurology Neurons Nimodipine Outcome Pathologic Processes Patients Performance Pharmaceutical Preparations Pharmacodynamics Phase Phase Ib Clinical Trial Play Positioning Attribute Preparation Risk Role Route Safety Seizures Sensory Small Business Innovation Research Grant Stroke Structure Subarachnoid Hemorrhage Survivors Synapses Therapeutic Traumatic Brain Injury Vasospasm antagonist arm cerebral hypoperfusion clinically translatable cognitive performance cytokine disability dose information drug candidate follow-up functional decline functional improvement functional outcomes improved mortality nervous system disorder neuroinflammation neurotoxic novel novel therapeutic intervention phase II trial pilot trial preclinical efficacy repaired response small molecule success therapeutic target

项目摘要

ABSTRACT Nontraumatic (aneurysmal) subarachnoid hemorrhage (aSAH) is one of the most dangerous forms of stroke, with almost half of victims dying within the first month after diagnosis, and a half of the survivors becoming severely disabled and incapable of living independently. This proposal is focused on addressing a common pathophysiological mechanism of neurocognitive outcomes of aSAH and other acute and chronic brain injuries – dysregulated overproduction of proinflammatory cytokines in the brain. Despite advances in our understanding of molecular neuroinflammatory mechanisms underlying adverse neuronal sequelae of acute and chronic brain injuries, approved therapeutics that target this pathological process are lacking. ImmunoChem Therapeutics (ICT) proposes to advance MW189, a novel small molecule anti-inflammatory experimental drug which has already successfully completed phase 1a and phase 1b clinical trials, as a candidate for a disease-modifying therapy for aSAH. MW189 is a selective suppressor of injury- and disease- induced proinflammatory cytokine overproduction associated with destructive glia inflammation/synaptic dysfunction cycles and their long-term neurotoxic effects. This proposed Fast-Track SBIR will deliver a phase 2a trial-ready drug and the corresponding regulatory documentation portfolio for a future pilot trial in aSAH. Specifically, we will: 1. Extend preclinical efficacy and pharmacodynamic data, and obtain the dosing and drug exposure information required to support a future phase 2a proof-of-concept clinical study in aSAH patients; 2. Produce and validate a GMP batch of the drug product from the existing cGMP drug substance (API) supply at a qualified Contract Manufacturing Organization (CMO); and 3. Prepare and submit an amendment to the open MW189 IND for a phase 2a clinical trial in aSAH patients. The Fast-Track structure will allow us to immediately move from proof of feasibility to SBIR Phase II activities that flow seamlessly from preparation of the Phase 2 trial-ready drug product to essential regulatory milestones for a future first-in-patient aSAH trial. Successful execution of the proposed project will position MW189 for immediate entry into a pilot proof-of-concept phase 2 trial in aSAH patients that will include pharmacokinetics and a pharmacodynamic arm. The success in that trial will, in turn, make MW189 a first-in-class drug candidate with a potential to become a novel therapeutic approach to SAH and other acute and chronic neurological disorders that involve dysregulated neuroinflammation as a driver of disease progression.

抽象的非创伤性（动脉瘤）亚蛛网膜下腔出血（asah）是中风的最危险形式之一，诊断后的第一个月，几乎一半的受害者死亡，而一半的生存开始严重残疾和无法独立生活。该提案的重点是解决神经认知结果的常见病理生理机制 ASAH和其他急性和慢性脑损伤 - 促炎细胞因子的过量产生失调在大脑中。尽管我们了解了我们对分子神经炎症机制的理解急性和慢性脑损伤的不良神经元后遗症，批准的疗法，以此为目标缺乏病理过程。免疫化学疗法（ICT）提出提高MW189的建议，这是一种新型的小分子抗炎已经成功完成1A期和1B期临床试验的实验药物作为A 疾病改良疗法的ASAH候选者。 MW189是损伤和疾病的选择性抑制剂诱导的促炎细胞因子过量产生与破坏性神经胶质注射/突触功能障碍周期及其长期神经毒性作用。拟议的快速轨道SBIR将提供一个阶段 2A可以试用的药物和相应的监管文件投资组合，用于未来在asah进行的试点试验。具体来说，我们将： 1。扩展临床前效率和药效学数据，并获得剂量和药物暴露支持未来2A阶段概念验证临床研究所需的信息； 2。从现有的CGMP药物（API）供应中生产并验证GMP批次在合格的合同制造组织（CMO）上；和 3。准备并提交一项修正案，以在ASAH患者的2A期临床试验中为Open MW189 IND进行修订。快速轨道结构将使我们立即从可行性证明转向SBIR II期活动从准备2期试用药物的制备到基本调节里程碑，无缝流动对于将来的初次访问ASAH试验。拟议项目的成功执行将使MW189定位立即进入ASAH患者的概念验证2期试验，其中将包括药代动力学和一个药效臂。该试验的成功又将使MW189成为一流的毒品候选人有可能成为SAH和其他急性和慢性神经系统的新型热方法作为疾病进展的驱动力的神经炎症失调的疾病。