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

• 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
• 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' 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

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（动脉瘤性）蛛网膜下腔出血（aSAH）是最危险的中风形式之一， 几乎一半的受害者在诊断后的第一个月内死亡，一半的幸存者成为 严重残疾，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 - 促炎细胞因子过度产生失调 在大脑中。尽管我们对分子神经炎症机制的理解取得了进展 急性和慢性脑损伤的不良神经元后遗症，已批准针对此的治疗方法 缺乏病理过程。 免疫化学疗法 (ICT) 提议开发 MW189，一种新型小分子抗炎药物 实验药物已成功完成1a期和1b期临床试验，作为 aSAH 疾病缓解疗法的候选者。 MW189 是损伤和疾病的选择性抑制剂 诱导促炎细胞因子过量产生，与破坏性神经胶质炎症/突触相关 功能障碍周期及其长期神经毒性作用。拟议的快速通道 SBIR 将提供一个阶段 2a 可供试验的药物以及用于未来 aSAH 试点试验的相应监管文件组合。 具体来说，我们将： 1. 扩展临床前疗效和药效数据，获得给药剂量和药物暴露量 支持未来针对 aSAH 患者的 2a 期概念验证临床研究所需的信息； 2. 从现有 cGMP 原料药 (API) 供应中生产并验证一批 GMP 药品 在合格的合同制造组织 (CMO) 中；和 3. 准备并提交针对 aSAH 患者的 2a 期临床试验的开放式 MW189 IND 修正案。 快速通道结构将使我们能够立即从可行性证明转向 SBIR 第二阶段活动 从准备第二阶段试验药物产品到重要监管里程碑的无缝流程 未来首次住院 aSAH 试验。拟议项目的成功执行将使 MW189 立即进入 aSAH 患者的概念验证阶段 2 试验，其中包括药代动力学 和药效学组。该试验的成功反过来将使 MW189 成为一流的候选药物 有潜力成为 SAH 和其他急慢性神经系统疾病的新型治疗方法 涉及神经炎症失调作为疾病进展驱动因素的疾病。