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，预计将增加在接下来的几十年里，预防、治愈或减缓疾病进展的有效疗法将显着增加。迫切需要具有独立药理功能的多样化新治疗策略。我们建议重新定位现有的急性脑损伤临床候选药物 MW189，目前正处于第 2 阶段。出血性中风的重症监护医学测试在临床中重新定位候选治疗药物。开发或已批准药物的重新利用通常被认为是更快、更有效的方法与从头开始的中枢神经系统药物发现和开发相比，需要注意的是完成后的成功率较低。跨疾病适应症（例如，从肿瘤学到神经病学）与同一疾病适应症内的重新定位。 MW189 将使用现有的 CNS 药物开发组合和研究基础设施。 MW189 是一种中枢神经系统渗透性小分子，可选择性地快速过渡到 AD 患者的临床评估。减轻应激源引起的细胞因子产生失调的变化，从而产生病理生理学。 MW189 导致多种疾病中的突触功能障碍、神经变性和认知能力下降。在支持 IND 的临床前安全药理学和毒理学方面没有责任，并成功完成了三项安全性、耐受性、药代动力学和药效学终点参与的 1 期临床研究。 MW189 在 FDA 指导的临床前和临床研究中的出色表现为 MW189在其他中枢神经系统疾病领域的临床开发继续进行，我们勇敢地说MW189是可行的。我们建议进行研究以消除剩余的技术。 MW189 进入未来 AD 临床研究的监管障碍。目标1：生产GMP临床原料药、制剂、对照品和内标。口服给药的临床药物将符合 FDA 2 期 IND 质量标准，并将满足 FDA 最近的要求关于提高药品质量的新指南。目标 2：在恢复期和恢复期的大鼠（6 个月）和狗（9 个月）中进行扩展的 GLP 毒理学研究毒代动力学结果将使 AD 患者能够每日口服给药并提供精确的剂量。长期管理的参数。目标 3：获得早期 AD 和相关痴呆症未来临床试验的 2 期 IND。使我们能够立即开展未来针对 AD 患者的 2a 期临床研究。拟议的研究和后续临床试验的成功结果将影响许多细胞因子失调是疾病进展或易感性机制的一部分的中枢神经系统疾病。