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: 9902254
• 负责人: JAMES G. MOE
• 金额: $ 100万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902254
• 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; Dementia; 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缓解疾病的小分子药物 具有 tau 病理学特征的阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD)。有一个关键未满足 需要一种治疗 AD 的疾病缓解药物 (DMD)。慢性病治疗策略需要安全、有效和 经济上可行的方法，例如小分子药物。该计划正在不断发展以满足这一需求 如果 DMD 成功的话，将对超过 500 万美国人产生巨大影响 目前有AD（预计到2050年将达到1600万）及其照顾者，这将有助于减少当前的AD 给我们国家造成 2590 亿美元的损失（预计到 2050 年将达到 1.1 万亿美元）。该公司正在开发小型 用于 AD 的分子 DMD 靶向 tau 聚集的初始步骤，导致 tau 寡聚物的形成， 有毒的 tau 蛋白聚集会导致神经元损失和记忆形成受损。我们假设 通过瞄准 tau 自缔合的第一步，所有形式的 tau 聚集体都应该减少。事实上，我们 在 Peter Davies 独立进行的一项盲法研究中，已经证明了体内概念验证， 博士，tau 生物学和治疗发现领域的思想领袖。我们的先导化合物 程序抑制表达人类 tau (htau) 的转基因小鼠中的 tau 聚集，最能代表 tau AD 中的聚合。重要的是，该铅具有良好的中枢神经系统药物特性，并已表现出良好的效果。 体外和体内初步安全筛选的安全性概况。在此，我们建议推进这一领先地位 化合物到 IND 的研究。在项目的第一阶段，我们的分包商奥尔巴尼分子 Research, Inc.（AMRI，纽约州奥尔巴尼）将开发放大方法、分析方法并合成 500 克 我们的先导化合物（第一阶段里程碑 1）。该计划将由我们的化学和制造部门监督 控制顾问（Edward Cheesman，博士）。然后我们的分包商 Toxikon 将使用该材料， Inc.（马萨诸塞州贝德福德）。开展单剂量大鼠PK研究和14天非GLP初步毒理学研究 大鼠（第一阶段里程碑 2）。第一阶段里程碑的成功完成将证明该计划进入 第二阶段，包括进行所有 GLP 遗传毒性测试、安全药理学和一般毒理学 对大鼠和狗这两个物种进行的研究。 Oligomerix 将管理该项目，验证该药物的体外功效 合成化合物，并分析和报告数据。在整个计划中，Oligomerix 将与 监管顾问（Joseph Kozikowski，医学博士）制定监管策略并召开 IND 前会议 与 FDA 合作。拟议的目标将使先导化合物进入临床前开发阶段并 将定义完成 IND 包所需进行的药代动力学和毒理学研究 为FDA。开发用于抑制 tau 寡聚化的 DMD 提供了一种重要、新颖且可行的方法 解决 AD 和 ADRD 破坏性影响的方法。