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

摘要 阿尔茨海默病(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戏剧性地。预防、治愈或减缓疾病进展的有效疗法是 缺乏。具有不同药理功能的多样化治疗策略组合迫在眉睫 需要的。我们建议重新定位现有的急性脑损伤临床候选药物MW189，目前处于第二阶段 出血性中风的重症监护医学检测。治疗候选药物在临床上的重新定位 开发或改变已批准药物的用途通常被认为是更快、更有效的方法。 比新的中枢神经系统药物的发现和开发。需要注意的是，完成后成功率较低 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对比。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。交付成果将允许 阿尔茨海默病患者快速过渡到临床评估。MW189是一种中枢神经系统渗透剂，小分子选择性地 减轻应激源引起的失调细胞因子产生的变化。由此产生的病理生理学 在各种疾病中导致突触功能障碍、神经变性和认知能力下降。MW189拥有 在IND-Enabling临床前安全性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第一阶段临床研究。 MW189的S在FDA指导的临床前和临床研究中的出色表现为 继续在其他中枢神经系统疾病领域开展MW189临床研究。我们假设MW189是一种可行的 适合痴呆症患者日常口服治疗。我们建议进行研究，以消除剩余的技术问题 以及MW189进入未来AD临床研究的监管障碍。 目的1：生产GMP临床药材、药品、参比标准品和内标。GMP 口服临床药物将符合FDA第二阶段INDS的质量标准，并将满足FDA最近的要求 关于提高药品质量的新指南。 目的2：对处于恢复期的大鼠(6个月)和狗(9个月)进行扩展的GLP毒理学研究 毒物动力学。结果将允许未来AD患者每日口服，并提供精细化的剂量 长期给药的参数。 目的3：获得2期IND，用于AD早期及相关痴呆的临床试验。这最后的里程碑将 让我们立即进入未来AD患者的2a期临床研究。 拟议研究和后续临床试验的成功结果将影响到一些 中枢神经系统疾病，细胞因子失调是疾病进展或易感机制的一部分。

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.