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

开发一种针对癫痫和阿尔茨海默病风险的新型抗神经炎症实验疗法

• 批准号: 10255597
• 负责人: Jennifer A Kearney
• 金额: $ 45.04万
• 依托单位: IMMUNOCHEM THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10255597
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Animal Model; Attenuated; Biological; Brain; Central Nervous System Diseases; Clinical; Clinical Treatment; Clinical Trials; Cognitive deficits; Data; Dementia; Development; Disease; Disease Progression; Dose; Drug Kinetics; Elderly; Encephalitis; Epilepsy; Etiology; Exhibits; Frequencies; Functional disorder; Funding; Future; GMP lots; Impaired cognition; Incidence; Individual; Inflammation; Injury; Intractable Epilepsy; Investigational Therapies; Link; Modeling; Molecular; Mus; Nervous System Trauma; Neuroglia; Neurons; Oral; Pathologic Processes; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase Ib Clinical Trial; Plasma; Population; Preparation; Prevalence; Production; Public Health; Recording of previous events; Recurrence; Risk; Risk Factors; Safety; Scheme; Seizures; Severities; Small Business Innovation Research Grant; Structure; Symptoms; Synapses; Technology Transfer; Therapeutic; Time; age group; age related; analog; arm; clinical development; cognitive performance; comorbidity; cytokine; dementia risk; dose information; drug production; first-in-human; high risk; improved; nervous system disorder; neuroinflammation; neurotoxic; non-demented; novel; novel therapeutics; patient safety; phase II trial; preclinical efficacy; small molecule; success; therapeutic target; treatment trial

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.

抽象的 阿尔茨海默氏病和癫痫是常见的与年龄有关的中枢神经系统疾病。阿尔茨海默氏病和 与其他任何年龄段相比，癫痫病的频率更高，并且癫痫病史是一种风险 阿尔茨海默氏症和相关痴呆症的发展因素。此外，阿尔茨海默氏病的患者患有 无端的癫痫发作和癫痫病的速度明显高于非痴呆率。这些公共卫生 相关性在病理生理和表现出的符号的水平上可见。例如，认知 损伤是阿尔茨海默氏病的确切方面，复发性癫痫发作与 认知障碍。显然，世界人口老龄化的增加使这种合并症成为主要的 忧虑。该建议的重点是解决阿尔茨海默氏症和 癫痫 - 促炎性细胞因子产生失调。促炎性细胞因子过量生产过多 替代激活的神经胶质是导致随后的中性损害和认知缺陷的原因 癫痫/癫痫发作疾病以及阿尔茨海默氏症和相关痴呆症。尽管我们的理解取得了进步 在中枢神经系统疾病中的这些分子神经炎症机制中， 缺乏针对这种病理过程的批准治疗。免疫化学治疗学（ICT） 提出提高MW189的建议，MW189是一种已经在早期临床发育中的新型小分子候选者 成功完成了1A期和1B期临床试验。 MW189是一个选择性抑制器 损伤和疾病诱导的促炎细胞因子与破坏性神经胶质有关 炎症/突触功能障碍循环及其长期神经毒性作用。这提出了快速轨道 SBIR将提供2A期试用的投资组合，以供将来的第一名（FIP）癫痫治疗试验。 具体来说，我们将：1。开发经过验证的GMP临床级药物的商业规模版本 方法，生产多kg药物批次，并获得未来患者临床试验的释放， 2。获取用于剂量信息的临床前效率数据和支持未来所需的生物学原理 第2A阶段概念验证研究对耐药性癫痫患者，3。准备所需的文件和 在患有耐药性癫痫患者的患者中提交第2阶段IND进行未来的临床试验。 我们的里程碑及其相关的关键任务被组织为SBIR I期活动（01年）和SBIR 第二阶段活动（02-03年）。快速轨道结构将使我们能够立即移动到SBIR II期 从准备和技术转移到基本里程碑的无缝流动的活动 安全试验，包括药代动力学和药效臂。成功还将进一步脱离风险MW189 对于未来的2阶段试验，阿尔茨海默氏病或​​其他与年龄相关的疾病涉及失调的疾病 神经炎症作为疾病进展的驱动力。