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

摘要 非创伤性(动脉瘤性)蛛网膜下腔出血(ASAH)是中风最危险的形式之一， 几乎一半的受害者在确诊后的第一个月内死亡，一半的幸存者成为 严重残疾，不能独立生活。 这项建议的重点是解决神经认知结果的一种常见的病理生理机制。 ASAH和其他急性和慢性脑损伤--促炎细胞因子的异常过度产生 在大脑里。尽管我们对潜在的分子神经炎性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，针对此的经批准的治疗方法 缺乏病理过程。 免疫化学疗法(ICT)建议开发新型小分子抗炎药物MW189 已成功完成1a期和1b期临床试验的实验药物 ASAH疾病修正疗法的候选人。MW189是一种选择性的损伤和疾病抑制因子 诱导性促炎细胞因子过度产生与破坏性胶质细胞炎症/突触相关 功能障碍周期及其长期神经毒性效应。这一建议的快速通道SBIR将提供一个阶段 2a可供试验的药物和相应的管理文件组合，以供今后在ASAH进行试点试验。 具体来说，我们会： 1.扩展临床前疗效和药效学数据，获得剂量和药物暴露 支持ASAH患者未来2a期概念验证临床研究所需的信息； 2.从现有的cGMP原料药(原料药)供应中生产并验证一批GMP药品 在合格的合同制造组织(CMO)；以及 3.准备并提交针对ASAH患者的2a期临床试验的开放的MW189 IND的修正案。 快速通道结构将使我们能够立即从可行性证明转移到SBIR第二阶段活动 从第二阶段试验就绪药物产品的准备到基本的监管里程碑的无缝流动 用于未来的首个住院患者ASAH试验。拟议项目的成功执行将使MW189 立即进入ASAH患者的试验性概念验证第二阶段试验，该试验将包括药代动力学 还有一个药效学手臂。该试验的成功将反过来使MW189成为一流的候选药物 有可能成为治疗SAH和其他急慢性神经系统疾病的新方法 包括失调的神经炎症在内的疾病，是疾病进展的驱动力。

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.