Tau Oligomer Platform Validation Using Lead Series Candidate in htau Mice

 描述(由申请人提供)：由于人口老龄化导致的人口结构变化，阿尔茨海默病(AD)的患病率在全球范围内呈上升趋势。它是美国最昂贵的疾病，每年直接造成的经济负担超过226亿美元 预计到2050年，这一数字将增加到1万亿美元。如果阿尔茨海默病的发病即使推迟几年，改变临床进程和延缓症状进展的疾病修改药物每年可以减少数百亿美元的经济负担。到目前为止，所有基于淀粉样蛋白假说的已完成的3期临床研究都未能达到其临床终点，这突显了开发AD治疗的替代方法的迫切需要。该公司正在开发治疗AD的治疗疾病的小分子药物，目标是导致tau寡聚体形成的tau聚集的第一步，tau寡聚体是导致神经元丢失和记忆形成障碍的有毒tau聚合体。竞争程序使用方法来选择抑制tau纤维或大集合体形成的化合物，以前被认为是毒性最大的tau物种。我们假设，通过瞄准tau自结合的第一步，所有形式的tau聚集体都应该减少。该项目的长期目标是将AD的疾病修改药物推向临床研究和市场。这项提案的目的是验证我们针对tau低聚物形成的小分子发现平台。我们领先系列化合物中的顶级候选化合物将用于在htau小鼠模型中展示靶向参与。该计划的目的是：1)从我们的先导系列中选择一种化合物用于体内研究；2)生产和配制用于体内研究的选定化合物；3)在htau小鼠模型中展示靶向参与。组织学和生化分析将用于评估化合物在体内减少tau病理的有效性。据估计，美国仅有一种疾病的治疗药物在推出第一年的销售额超过5亿美元，并在推出后10年内超过100亿美元。商业化战略是与一家大型制药公司建立战略合作伙伴关系，以加速进入临床研究和市场。值得注意的是，该公司目前正在与三家不同的大型制药公司谈判合作事宜。该项目将与彼得·戴维斯博士合作，他是阿尔茨海默病tau病理研究的主要思想领袖和世界知名专家，htau小鼠模型就是在他的实验室开发出来的。

 DESCRIPTION (provided by applicant): The prevalence of Alzheimer's disease (AD) is increasing worldwide due to demographic shifts resulting from an aging population. It is the most costly disease in the US with a financial burden of over $226 billion annually in direct costs that are estimated to increase to $1 trillion by 2050. Disease-modifying drugs that change the clinical course and delay symptomatic progression could reduce the economic burden by multiples of tens of billions of dollars per year if the onset of AD is delayed even a few years. To-date, all completed phase 3 clinical studies based on the amyloid hypothesis have failed to meet their clinical endpoints underscoring the critical need for alternative approaches for the development of AD therapeutics. The Company is developing disease-modifying small molecule drugs for AD that target the initial step in tau aggregation leading to the formation of tau oligomers, the toxic tau aggregates responsible for neuronal loss and impairment of memory formation. Competing programs use methods to select compounds inhibiting the formation of tau fibrils or large aggregates, previously thought to be the most toxic tau species. We hypothesized that by targeting the first step in tau self-association all forms of tau aggregates should be reduced. The long-term goal of the project is to advance disease-modifying drugs for AD to clinical studies and the market. The objective of this proposal is to validate our small molecule discovery platform targeting tau oligomer formation. The top candidate from our lead series of compounds will be used to demonstrate target engagement in the htau mouse model. The program aims are to 1) Select a compound from our lead series for the in vivo study 2) Produce and formulate the selected compound for the in vivo study 3) Demonstrate target engagement in the htau mouse model. Histological and biochemical analyses will be used to assess efficacy of compound for the in vivo reduction of tau pathology. Estimates show U.S only sales for a disease modifying therapeutic in the first year of launch of greater than $0.5 billion and surpassing $10 billion within 10 years post launch. The commercialization strategy is to form a strategic partnership with a large pharmaceutical company to accelerate to clinical studies and to the market. Significantly, the Company is now negotiating a collaboration with three different large pharma companies. This program will collaborate with Dr. Peter Davies, a major thought leader and world renowned expert in the study of tau pathology in Alzheimer's disease and in whose lab the htau mouse model was developed.