Development of a novel anti-neuroinflammatory experimental therapeutic for epilepsy and Alzheimer's risk

摘要 阿尔茨海默病和癫痫是常见的年龄相关的中枢神经系统疾病。老年痴呆症和 癫痫是更常见的老年人相比，任何其他年龄组，和癫痫病史是一个风险 阿尔茨海默氏症和相关痴呆症的发展因素。此外，阿尔茨海默病患者 无端癫痫发作和癫痫的发生率明显高于非痴呆老年人。这些公共卫生 在病理生理学和表现症状的水平上可以看到相关性。例如认知 损伤是阿尔茨海默病的一个明确方面，反复发作的癫痫发作与 认知障碍显然，世界人口老龄化的加剧使科摩罗成为一个主要的 关心这项建议的重点是解决一个共同的病理生理机制，在阿尔茨海默氏症和 癫痫-促炎细胞因子产生失调。促炎细胞因子过度产生 异常激活的神经胶质细胞是导致随后的神经损伤和认知缺陷的因素， 癫痫/癫痫发作病症和阿尔茨海默氏症及相关痴呆中的治疗。尽管我们的理解有了进步 在CNS疾病中的不利神经元后遗症的这些分子神经炎性机制中， 缺乏靶向这种病理过程的经批准的治疗剂。免疫化学治疗（ICT） 建议推进MW 189，一种已经处于早期临床开发阶段的新型小分子候选物， 已成功完成1a期和1b期临床试验。MW 189是一种选择性抑制剂， 损伤和疾病诱导的与破坏性胶质细胞相关的促炎细胞因子过度产生 炎症/突触功能障碍周期及其长期神经毒性作用。这条快速通道 SBIR将为未来的首次患者（FIP）癫痫治疗试验提供2a期试验准备组合。 具体来说，我们将：1。开发经验证的GMP临床级药物生产的商业规模版本 方法，生产多Kg原料药批次，并获得其放行用于未来的患者临床试验， 2.获得临床前有效性数据，以获得给药信息和支持未来研究所需的生物学依据。 在耐药性癫痫患者中进行的2a期概念验证研究，3.准备所需文件， 提交2期IND，用于未来在耐药性癫痫患者中进行临床试验。 我们的里程碑及其相关的关键任务被组织为SBIR第一阶段活动（01年）和SBIR 第二阶段活动（02-03年）。快速通道结构将使我们能够立即进入SBIR第二阶段 从准备和技术转让到未来FIP的重要里程碑， 安全性试验，包括药代动力学和药效学组。成功也将进一步降低风险MW 189 用于未来阿尔茨海默病或其他与年龄相关的疾病的2期试验， 神经炎症作为疾病进展的驱动因素。

ABSTRACT Alzheimer’s disease and epilepsy are common age-related CNS disorders. Both Alzheimer’s disease and epilepsy are more frequent in the elderly compared to any other age groups, and a history of epilepsy is a risk factor for development of Alzheimer’s and related dementias. Further, patients with Alzheimer’s disease have unprovoked seizures and epilepsy at a significantly higher rate than non-demented elderly. These public health correlations are seen at the level of pathophysiology and manifested symptoms. For example, cognitive impairment is a definitive aspect of Alzheimer’s disease, and recurrent epileptic seizures are associated with cognitive impairment. Clearly, the increase in aging of the world’s population makes this comorbidity a major concern. This proposal is focused on addressing a common pathophysiological mechanism in Alzheimer’s and epilepsy – dysregulated proinflammatory cytokine production. Proinflammatory cytokine overproduction from abnormally activated glia is a contributor to subsequent neurological damage and cognitive deficits in both epilepsy/seizure disorders and in Alzheimer’s and related dementias. Despite advances in our understanding of these molecular neuroinflammatory mechanisms underlying adverse neuronal sequelae in CNS disorders, approved therapeutics that target this pathological process are lacking. ImmunoChem Therapeutics (ICT) proposes to advance MW189, a novel small molecule candidate already in early phase clinical development, having successfully completed phase 1a and phase 1b clinical trials. 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 portfolio for future first-in-patient (FIP) epilepsy treatment trials. Specifically, we will: 1. Develop a commercial-scale version of a validated GMP clinical grade drug production approach, produce a multi-Kg drug substance lot, and obtain its release for future patient clinical trials, 2. Obtain preclinical efficacy data for dosing information and the biological rationale required to support future phase 2a proof-of-concept studies in patients with drug-resistant epilepsy, 3. Prepare required documents and submit a phase 2 IND for a future clinical trial in patients with drug-resistant epilepsy. Our milestones and their associated key tasks are organized as SBIR Phase I activities (year 01) and SBIR Phase II activities (years 02-03). The Fast-Track structure will allow us to immediately move to SBIR Phase II activities that flow seamlessly from preparation and technology transfer to essential milestones for a future FIP safety trial including pharmacokinetics and a pharmacodynamic arm. Success will also further de-risk MW189 for future phase 2 trials in Alzheimer’s disease or other age-related disorders that involve dysregulated neuroinflammation as a driver of disease progression.