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善疾病的小分子药物， 阿尔茨海默病（AD）和AD相关痴呆（ADRD）与tau病理。有一个关键的未满足的 需要一种治疗AD的疾病修饰药物（DMD）。慢性治疗策略需要安全，有效， 经济上可行的方法，如小分子药物。该计划正在进行，以满足这一需求 如果成功的话，将对500多万美国人产生巨大的影响， 目前有AD（预计到2050年将达到1600万）及其护理人员，并将有助于减少目前的 2590亿美元的成本（预计到2050年将达到1.1万亿美元）。公司正在开发一种小型 用于AD的分子DMD，其靶向导致tau寡聚体形成的tau聚集的初始步骤， 毒性tau聚集体导致神经元损失和记忆形成的损害。我们假设 通过靶向tau自结合的第一步，所有形式的tau聚集体都应该减少。其实我们 在Peter Davies独立进行的盲法研究中， 哲学博士、tau生物学和治疗发现领域的思想领袖。我们的实验室里的铅化合物 程序抑制了表达人tau（htau）的转基因小鼠中的tau聚集， AD中的聚集。重要的是，该先导化合物具有良好的CNS药物样性质，并已证明具有良好的 体外和体内初步安全性筛选中的安全性特征。在这里，我们建议推进这一领先优势， 化合物到IND使能研究。在项目的第一阶段，我们的分包商奥尔巴尼分子公司 research公司(AMRI，奥尔巴尼，纽约）将开发放大方法，分析方法和合成500克的 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监督 控制顾问（Edward Cheesman博士）。该材料将由我们的分包商Toxikon使用， Inc.（贝德福德，MA）。进行单次给药大鼠PK研究和14天非GLP初步毒理学研究， 大鼠（I期里程碑2）。第一阶段里程碑的成功完成将证明该计划进入 II期，包括进行所有GLP遗传毒性试验、安全药理学和一般毒理学 在两个物种中进行的研究，大鼠和犬。Oligomerix将管理该项目，确认 合成化合物，并分析和报告数据。在整个计划中，Oligomerix将与一个 监管顾问（Joseph Kozikowski，MD）制定监管策略并召开IND前会议 和食品药物管理局拟议的目标将使先导化合物能够进入临床前开发， 将定义完成IND包装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提供了一种关键的、新颖的和可行的方法。 这是一个解决AD和ADRD破坏性影响的方法。