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治疗疾病的小分子药物 阿尔茨海默病(AD)和与AD相关的痴呆(ADRD)伴tau病理。有一个严重的未满足的问题 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、有效和 经济上可行的方法，如小分子药物。该计划正在取得进展，以满足这一需求 如果DMD成功，将对500多万美国人产生巨大影响 目前有AD(预计到2050年将达到1600万)和他们的照顾者，并将有助于减少目前的 2590亿美元(预计到2050年将达到1.1万亿美元)。该公司正在开发一种小型 AD的分子DMD，靶向tau聚集的初始步骤，导致tau低聚物的形成， 有毒的tau聚集体导致神经元丢失和记忆形成障碍。我们假设 通过瞄准tau自缔合的第一步，应该减少所有形式的tau聚集体。事实上，我们 在彼得·戴维斯独立进行的一项盲目研究中，他们在体内证明了概念的正确性， 博士，tau生物学和治疗发现领域的思想领袖。来自我们的先导化合物 程序抑制了表达人tau(Htau)的转基因小鼠的tau聚集，最好地代表了tau AD中的聚合。重要的是，该铅具有良好的中枢神经系统类药物性质，并已表现出良好的 体外和活体初步安全筛选的安全性概况。在这里，我们建议将这一领先优势 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，Inc.(Amri，Albany，NY)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)。然后这种材料将被我们的分包商Toxikon使用， 公司(马萨诸塞州贝德福德)进行大鼠单次PK试验和14天非GLP初步毒理学试验 RAT(第一阶段里程碑2)。第一阶段里程碑的成功完成将证明将该计划转移到 第二阶段，包括进行所有普洛斯遗传毒性测试、安全药理学和一般毒理学 在两个物种上的研究，老鼠和狗。寡聚将管理该项目，鉴定该药物的体外疗效 合成化合物，并对数据进行分析和报告。在整个计划中，寡聚将与一个 监管顾问(约瑟夫·科齐科夫斯基，医学博士)，制定监管战略并召开IND前会议 与食品药品管理局合作。拟议的目标将使先导化合物能够进入临床前开发阶段，并 将确定完成IND包所需进行的药代动力学和毒理学研究 为食品和药物管理局。开发一种用于抑制tau齐聚的DMD提供了一种关键的、新颖的和可行的 应对AD和ADRD破坏性影响的方法。