Development and Commercialization of a Tau Oligomer Inhibitor for AD/RD

项目摘要：这个R44补充版的应用是集中开发的一个全面的 出版战略，以满足该公司的长期目标，即向科学工作者传播其研究成果 社区。拟议的工作旨在为公司制定长期出版计划，该计划将 包括在项目期限内撰写和出版(2)手稿。阿尔茨海默病的发病率是 在全球范围内不断增加。仍然迫切需要性价比高的AD疾病修饰药物 而且易于管理。这项计划正在取得进展，以满足经济的、疾病修正的需求 稳定的、口服的、可自行给药的药物。如果成功，它将对 目前患有AD的美国人超过650万(预计到2050年将达到1270万)，他们的 护理人员，并将帮助降低我们目前3210亿美元的成本(预计到2050年将达到1万亿美元) 国家(阿尔茨海默病协会，2022年阿尔茨海默病事实和数字)。我们现在已经完成了所有 为我们的人类首个1a期研究向FDA申请IND的临床前工作，以及我们的IND申请 已于2022年6月1日成功提交给食品和药物管理局(IND#156701)。工作总结如下：TO-0582 在两种tau病小鼠模型(含有人tau的htau模型)中显示了药理活性 在AD和具有P301L的JNPL3小鼠模型中，所有6个异构体都最能代表tau聚集 突变和代表四个重复的变态)，合理的药代动力学特征，最小的DDI 对心血管、肺部和中枢神经系统的潜在、缺乏/最小影响，以及缺乏遗传毒性。 在28天的大鼠和狗的GLP毒性研究中，观察到相对温和的非不良毒性。这一号 大鼠和狗28天研究的不良反应水平都是测试的最高剂量。因此，TO-0582是一个 是治疗神经退行性疾病临床开发的极佳候选者。制造 用于非临床安全性研究(NCS)和药物配方前工作的千克数量已经完成。 我们还为我们的药品OLX-07010的生产准备了一批GMP。这样做的目的是 补充目标是制定一项全面的出版战略，以完成传播任务 与科学界高度相关的新信息，以及写作、编辑审查和提交 科学手稿。这包括为AD和基于tau的开发制定差距分析 方案基于已发表的文献和对寡聚糖体的临床前数据的回顾。这一目标将 包括文献检索、编辑审查和提交手稿。作为国家老龄问题研究所 是联邦AD研究的主要机构，制定AD的DMT，具有最高的相关性 为了它的使命。

PROJECT SUMMARY: This R44 supplement application is focused on the development of a comprehensive publication strategy to meet the company’s long-standing goal of disseminating its findings to the scientific community. The proposed work is designed to create a long term publication plan for the company which will include the writing and publishing of (2) manuscripts during the project term. The prevalence of AD is increasing worldwide. There remains an urgent need for disease modifying drugs for AD that are cost-effective and easy to administer. This program is progressing to fill the need with an economical, disease-modifying drug that is stable, oral, and can be self-administered. If successful, it will have a tremendous impact on the more than 6.5 million Americans who currently have AD (projected to be 12.7 million by 2050) and their caregivers, and will help reduce the current cost of $321 billion (projected to be $1 trillion by 2050) to our nation (Alzheimer's Association 2022 Alzheimer's Disease Facts and Figures). We have now completed all preclinical work for our IND application to FDA for our first-in-human phase 1a study, and our IND application was successfully submitted to FDA on June 1, 2022 (IND # 156701). A summary of this work follows: TO-0582 demonstrated pharmacologic activity in two mouse models of tauopathy (the htau model that has human tau with all 6 isomers best representing tau aggregation in AD and in the JNPL3 mouse model that has a P301L mutation and represents four-repeat tauopathies), reasonable pharmacokinetic characteristics, minimal DDI potential, lack/minimal effects on cardiovascular, pulmonary and CNS systems, and a lack of genotoxicity. Relatively modest, non-adverse toxicity was observed in 28-day rat and dog GLP toxicity studies. The no adverse effect level for both the rat and dog 28 day studies were the highest dose tested. Thus, TO-0582 is an excellent candidate for clinical development for treatment of neurodegenerative diseases. Manufacture of kilogram quantities for non-clinical safety studies (NCSS) and drug pre-formulation work has been completed. A GMP batch was also prepared for the manufacture of our drug product OLX-07010. The goal of this supplemental aim is to create a comprehensive publication strategy that will fulfill the tasks of disseminating novel and highly relevant information to the scientific community, and writing, editorial review and submission of scientific manuscripts. This includes development of a gap analysis for AD and tau-based development programs based on published literature and a review of the body of Oligomerix’s pre-clinical data. This aim will include literature searches, editorial review and submission of manuscripts. As the National Institute on Aging is the primary Federal agency for AD research, the development of a DMT for AD, has the highest relevance for its mission.