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

摘要 非创伤性蛛网膜下腔出血（aSAH）是中风最危险的形式之一， 几乎一半的受害者在诊断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一个共同的病理生理机制的神经认知的结果 aSAH和其他急性和慢性脑损伤-促炎性细胞因子的过度生产失调 在大脑中。尽管我们对神经炎症的分子机制有了进一步的了解， 急性和慢性脑损伤的不良神经元后遗症，批准的靶向治疗 病理过程缺乏。 ImmunoChem Therapeutics（ICT）提议推进MW 189，一种新型小分子抗炎药 已经成功完成1a期和1b期临床试验的实验药物，作为 aSAH疾病缓解疗法的候选者。MW 189是损伤和疾病的选择性抑制剂， 与破坏性神经胶质炎症/突触相关的诱导的促炎细胞因子过度产生 功能障碍周期及其长期神经毒性作用。这一拟议的快速通道SBIR将提供一个阶段 2a试验准备药物和相应的监管文件组合，用于未来aSAH的试点试验。 具体而言，我们将： 1.扩展临床前有效性和药效学数据，并获得剂量和药物暴露 支持未来在aSAH患者中进行的2a期概念验证临床研究所需的信息; 2.从现有cGMP原料药（API）供应中生产并验证制剂的GMP批次 在合格的合同制造组织（CMO）;以及 3.为aSAH患者的2a期临床试验准备并提交一份开放的MW 189 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移到SBIR第二阶段活动 从2期临床试验药物产品的制备到重要的监管里程碑的无缝流程 用于未来的首次aSAH患者试验拟议项目的成功执行将使MW 189成为 立即进入aSAH患者的初步概念验证II期试验，包括药代动力学 该试验的成功反过来将使MW 189成为一流的候选药物 有可能成为SAH和其他急性和慢性神经系统疾病的新治疗方法 涉及神经炎症失调作为疾病进展驱动因素的疾病。

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.