GMP Production and Extended Toxicology of an Oral Formulation Drug for Alzheimer's Disease

治疗阿尔茨海默病的口服制剂药物的 GMP 生产和扩展毒理学

基本信息

批准号：
10624841
负责人：
LINDA J VAN ELDIK
金额：
$ 154.73万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624841
关键词：
Acute Acute Brain Injuries Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy Amendment American Area Attenuated Biological Brain Brain hemorrhage Canis familiaris Central Nervous System Diseases Chemistry Clinical Clinical Research Clinical Trials Critical Care Dementia Disease Disease Progression Disease susceptibility Dose Drug Formulations Formulation Foundations Functional disorder Future Human Impaired cognition Individual Inflammation Inflammatory Intervention Investigation Medicine Morbidity - disease rate Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurology Oncology Oral Oral Administration Outcome Patients Pharmaceutical Preparations Pharmacology and Toxicology Phase Placebos Positioning Attribute Production Public Health Qualifying Rattus Recovery Reference Standards Research Infrastructure Safety Scheme Stress Tests Synapses Testing Therapeutic Toxicokinetics Toxicology Work attenuation brain dysfunction capsule clinical candidate clinical development clinical investigation cytokine drug candidate drug development drug discovery drug quality effective therapy manufacture mortality novel therapeutic intervention pharmacokinetics and pharmacodynamics pharmacologic phase 3 study phase II trial preclinical safety preclinical study prevent programs research clinical testing safety study small molecule stability testing stressor success therapeutic candidate

项目摘要

ABSTRACT Alzheimer’s disease (AD) and related dementias are a major global public health problem, predicted to increase dramatically over the next decades. Effective therapies to prevent, cure, or slow the disease progression are lacking. A diversified portfolio of new therapeutic strategies with discrete pharmacological function is urgently needed. We propose repositioning of an existing acute brain injury clinical candidate, MW189, now in phase 2 critical care medicine testing for hemorrhagic stroke. Repositioning of therapeutic candidates in clinical development, or repurposing of approved drugs, are generally considered faster and more efficient approaches than de novo CNS drug discovery and development. Caveats include the lower success rates when done across disease indications (e.g., oncology to neurology) vs within the same disease indication. Repositioning of MW189 will use an existing CNS drug development portfolio and research infrastructure. Deliverables will allow rapid transition to clinical evaluation in AD patients. MW189 is a CNS-penetrant, small molecule that selectively attenuates stressor-induced changes in dysregulated cytokine production. The resultant pathophysiology contributes to synaptic dysfunction, neurodegeneration and cognitive decline in diverse diseases. MW189 has no liabilities in IND-enabling preclinical safety pharmacology and toxicology and successfully completed three phase 1 clinical studies of safety, tolerability, pharmacokinetics and pharmacodynamic end point engagement. MW189’s excellent profile in FDA guided preclinical and clinical studies provides a strong foundation for continued MW189 clinical development in other CNS disease areas. We hypothesize that MW189 is a viable candidate for daily oral treatment of dementia patients. We propose studies to remove the remaining technical and regulatory barriers to MW189 entry into future AD clinical investigations. Aim 1: Produce GMP clinical drug substance, drug product, reference standard and internal standard. GMP clinical drug for oral administration will be FDA quality compliant for phase 2 INDs and will address recent FDA new guidances on enhanced drug quality. Aim 2: Perform extended GLP toxicology studies in rats (6 mo) and dogs (9 mo) with recovery phase and toxicokinetics. Outcomes will allow future daily oral administration to AD patients and provide refined dosing parameters for longer term administration. Aim 3: Obtain a phase 2 IND for future clinical trials in early AD and related dementias. This final milestone will position us to immediately proceed to a future phase 2a clinical study of AD patients. Successful outcomes from the proposed investigations and the follow-on clinical trials will impact a number of CNS disorders where cytokine dysregulation is part of the disease progression or susceptibility mechanism.

抽象的阿尔茨海默氏病（AD）和相关痴呆症是一个主要的全球公共卫生问题，预计会增加有效预防，治愈或减慢疾病进展的疗法是缺乏。具有离散药物功能的新治疗策略的多元化投资组合是迫切的需要。我们建议重新定位现有的急性脑损伤临床候选者MW189，现在在第2阶段重症监护医学测试出血性中风。重新定位临床治疗候选者通常认为开发或重新利用批准的药物，更快，更有效的方法比从头cns的药物发现和开发。警告包括较低的成功率跨疾病的适应症（例如，神经学对神经病学）与相同疾病指示中的跨性别。重新定位 MW189将使用现有的CNS药物开发组合和研究基础设施。可交付成果允许快速过渡到AD患者的临床评估。 MW189是一种CNS-PENETRANT，小分子，有选择地减弱应激源引起的细胞因子产生失调的变化。由此产生的病理生理学导致潜水疾病的突触功能障碍，神经退行性变化和认知能力下降。 MW189有没有责任指导临床前安全药理学和毒理学，并成功完成了三个第1阶段的安全性，耐受性，药代动力学和药效终点参与的临床研究。 MW189在FDA指导的临床前和临床研究方面的出色概况为续MW189在其他中枢神经系统疾病地区进行临床发展。我们假设MW189是可行的每天口服痴呆症患者的候选人。我们建议研究删除其余技术 MW189进入未来AD临床研究的监管障碍。目标1：生产GMP临床药物，药物，参考标准和内标。 GMP 口服临床药物将在第2阶段IND中符合FDA质量，并将解决最近的FDA 有关增强药物质量的新指南。 AIM 2：在大鼠（6个月）和狗（9个月）中进行恢复阶段的扩展GLP毒理学研究有毒因素。结果将允许将来的每日口服给广告患者，并提供精致的剂量长期给药的参数。 AIM 3：获得第2阶段IND，以备早期AD和相关痴呆症的未来临床试验。这个最后的里程碑将定位我们立即进行AD患者的未来2A临床研究。拟议的调查和后续临床试验的成功结果将影响许多中枢神经系统疾病是细胞因子失调是疾病进展或敏感性机制的一部分。