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、治疗或减缓疾病进展的有效疗法包括 缺乏迫切需要具有离散药理学功能的新治疗策略的多样化组合 needed.我们建议重新定位现有的急性脑损伤临床候选人，MW189，现在处于第2阶段 出血性中风的重症监护药物测试临床候选治疗药物的重新定位 开发或重新利用已批准的药物通常被认为是更快、更有效的方法 而不是从头发现和开发中枢神经系统药物。警告包括较低的成功率时， 跨越疾病适应症（例如，肿瘤学到神经学）与相同疾病适应症内的比较。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。可拆卸部件将允许 在AD患者中快速过渡到临床评价。MW 189是一种CNS渗透剂小分子，可以选择性地 减弱应激物诱导的失调细胞因子产生的变化。由此产生的病理生理学 导致突触功能障碍、神经变性和各种疾病中的认知能力下降。MW189有 在IND使能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I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以下方面奠定了坚实的基础： 继续在其他CNS疾病领域进行MW189临床开发。我们假设MW189是一种可行的 痴呆症患者的日常口服治疗的候选人。我们建议进行研究， 以及MW189进入未来AD临床研究的监管障碍。 目的1：生产GMP临床原料药、制剂、参比标准品和内标。GMP 用于口服给药的临床药物将符合FDA 2期IND的质量要求，并将解决最近FDA 提高药品质量的新指南。 目的2：在大鼠（6个月）和犬（9个月）中进行扩展GLP毒理学研究（含恢复期）， 毒物代谢结果将允许AD患者未来每日口服给药，并提供精细的给药 长期管理的参数。 目标3：获得2期IND用于早期AD和相关痴呆的未来临床试验。这一最后的里程碑将 使我们能够立即进行AD患者的未来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许多 细胞因子失调是疾病进展或易感性机制的一部分的CNS疾病。

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.