Scale-up and Synthesis of a Tau Oligomer Inhibitor to initiate IND enabling studies for AD and ADRD

Tau 寡聚体抑制剂的放大和合成，启动 IND 使 AD 和 ADRD 研究成为可能

• 批准号: 9922201
• 负责人: JAMES G. MOE
• 金额: $ 99.99万
• 依托单位: OLIGOMERIX, INC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922201
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; American; Ames Assay; Biological Assay; Biology; Blinded; Blood; Canis familiaris; Cardiovascular system; Caregivers; Cause of Death; Cells; Chemistry; Chromosome abnormality; Chronic; Clinical; Cost of Illness; Data Reporting; Development; Direct Costs; Disease; Disease Progression; Doctor of Philosophy; Dose; Drug Kinetics; Economic Burden; Evaluation; Financial Hardship; Goals; Human; In Vitro; Lead; Lung; Medical; Memory impairment; Methods; Micronucleus Tests; Molecular; Mutagenicity Tests; Pathology; Pharmaceutical Preparations; Pharmacology; Phase; Prevalence; Process; Property; Rattus; Research; Safety; Sampling; Therapeutic; Therapeutic Intervention; Toxicogenetics; Toxicology; Transgenic Mice; United States; Work; advanced disease; analytical method; base; cost; cost effective; in vivo; inhibitor/antagonist; meetings; method development; mouse model; neuron loss; novel; pre-clinical; preclinical development; prevent; programs; research clinical testing; safety study; safety testing; scale up; small molecule; task analysis; tau Proteins; tau aggregation; treatment strategy

The long-term goal of this program is to develop a disease-modifying, small molecule drug for Alzheimer’s disease (AD) and AD related dementias (ADRD) with tau pathology. There is a critical unmet need for a disease-modifying drug (DMD) for AD. Chronic treatment strategies require safe, effective, and economically feasible approaches such as small molecule drugs. This program is progressing to fill this need with a DMD that, if successful, will have a tremendous impact on the more than five million Americans who currently have AD (projected to be 16 million by 2050) and their caregivers, and will help reduce the current cost of $259 billion (projected to be $1.1 trillion by 2050) to our nation. The Company is developing a small molecule DMD for AD that targets 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. We hypothesized that by targeting the first step in tau self-association all forms of tau aggregates should be reduced. In fact, we have demonstrated proof-of-concept in vivo, in a blinded study independently performed by Peter Davies, Ph.D., a thought leader in the field of tau biology and therapeutic discovery. The lead compound from our program inhibited tau aggregation in transgenic mice expressing human tau (htau), best representing tau aggregation in AD. Importantly, the lead has good CNS drug-like properties and has demonstrated a good safety profile in preliminary safety screens in vitro and in vivo. Here, we propose to advance this lead compound to IND enabling studies. During Phase I of the project our subcontractor, Albany Molecular Research, Inc. (AMRI, Albany, NY) will develop scale-up methods, analytical methods and synthesize 500 g of our lead compound (Phase I milestone 1). The program will be overseen by our Chemistry and Manufacturing Controls Consultant (Edward Cheesman, Ph.D.). This material will then be used by our subcontractor, Toxikon, Inc. (Bedford, MA). to carry out a single-dose rat PK study and 14 day non-GLP preliminary toxicology study in rat (Phase I milestone 2). Successful completion of the Phase I milestones will justify moving the program into Phase II, that includes carrying out all GLP genetic toxicity testing, safety pharmacology and general toxicology studies in two species, rat and dog. Oligomerix will manage the project, qualify the in vitro efficacy of the synthesized compound, and analyze and report the data. Throughout the program, Oligomerix will work with a regulatory consultant (Joseph Kozikowski, MD) to develop a regulatory strategy and to have a pre-IND meeting with the FDA. The proposed Aims will enable advancing the lead compound into pre-clinical development and will define the pharmacokinetic and toxicology studies that need to be performed to complete the IND package for the FDA. Developing a DMD for inhibition of tau oligomerization provides a crucial, novel, and viable approach to addressing the devastating impact of AD and ADRD.

该计划的长期目标是开发一种改良疾病的小分子药物 阿尔茨海默氏病（AD）和与AD相关的痴呆症（ADRD）患有TAU病理学。有一个关键的未安装 需要用于AD的疾病调整药物（DMD）。长期治疗策略需要安全，有效，并且 经济上可行的方法，例如小分子药物。该程序正在进步以满足这一需求 如果成功，如果成功，将对超过500万美国人产生巨大影响 目前有广告（预计到2050年为1600万）及其护理人员，将有助于减少当前 我们国家的成本为2590亿美元（预计到2050年为1.1万亿美元）。该公司正在开发一个小的 用于靶向tau聚集的初始步骤的AD的分子DMD，导致Tau低聚物的形成， 导致神经元丧失和记忆形成损害的有毒tau聚集体。我们假设 通过针对tau自我关联的第一步，应减少所有形式的tau聚集体。实际上，我们 在彼得·戴维斯（Peter Davies）独立进行的一项盲目研究中，体内证明了概念验证 博士学位，Tau生物学和治疗发现领域的思想领袖。我们的铅大院 程序抑制了表达人tau（HTAU）的转基因小鼠的tau聚集，最好代表tau 广告中的聚合。重要的是，铅具有良好的CNS药物样特性，并且表现出了很好 初步安全屏幕的安全性在体外和体内。在这里，我们建议推进这一领导 化合物以实现研究。在该项目的第一阶段，我们的分包商Albany Molecular Research，Inc。（AMRI，AMRI，纽约州奥尔巴尼）将开发规模化方法，分析方法和合成500克 我们的铅化合物（第一阶段里程碑1）。该计划将由我们的化学和制造业监督 控制顾问（Edward Cheesman，Ph.D。）。然后，我们的分包商Toxikon将使用此材料， Inc.（马萨诸塞州贝德福德）。进行单剂量大鼠PK研究和14天的非GLP初步毒理学研究 大鼠（第一阶段里程碑2）。成功完成I阶段里程碑将证明将程序转移到 第二阶段，其中包括进行所有GLP遗传毒性测试，安全药理学和一般毒理学 在两种物种中进行研究，大鼠和狗。寡头将管理该项目，符合体外效率 合成化合物，分析和报告数据。在整个程序中，寡聚将与 监管顾问（马里兰州约瑟夫·科西科夫斯基）制定监管策略并举行预先会议 与FDA。拟议的目标将使铅大院能够将铅化合物推向临床前的发展，并 将定义需要进行的药代动力学和毒理学研究，以完成IND包装 对于FDA。开发抑制tau低聚的DMD提供了至关重要，新颖且可行的 解决AD和ADRD毁灭性影响的方法。