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

项目摘要：该 R44 补充应用程序的重点是开发全面的 出版策略，以实现公司向科学界传播其研究结果的长期目标 社区。拟议的工作旨在为公司制定长期出版计划，该计划将 包括项目期间（2）稿件的撰写和出版。 AD 的患病率是 全球范围内不断增加。仍然迫切需要具有成本效益的 AD 疾病修饰药物 并且易于管理。该计划正在不断进展，以满足经济、疾病缓解的需求 药物稳定，口服，可以自行给药。如果成功的话，将会产生巨大的影响 目前有超过 650 万美国人患有 AD（预计到 2050 年将达到 1270 万） 并将有助于减少目前 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据）。我们现在已经完成了所有 我们向 FDA 提交的首次人体 1a 期研究 IND 申请的临床前工作，以及我们的 IND 申请 于2022年6月1日成功提交给FDA（IND#156701）。这项工作的摘要如下：TO-0582 在两种 tau 蛋白病小鼠模型（具有人类 tau 蛋白的 htau 模型）中显示出药理活性 所有 6 种异构体最能代表 AD 和具有 P301L 的 JNPL3 小鼠模型中的 tau 聚集 突变并代表四次重复 tau蛋白病），合理的药代动力学特征，最小的 DDI 潜在的，对心血管、肺和中枢神经系统的影响很少/最小，并且没有遗传毒性。 在 28 天的大鼠和狗 GLP 毒性研究中观察到相对温和的非不良毒性。没有 大鼠和狗28天研究的不良反应水平均为测试的最高剂量。因此，TO-0582 是 神经退行性疾病治疗临床开发的优秀候选者。制造 公斤量的非临床安全性研究（NCSS）和药物预配制工作已经完成。 还准备了 GMP 批次用于生产我们的药品 OLX-07010。此举的目标 补充目标是制定一项全面的出版战略，以完成传播的任务 与科学界高度相关的新颖信息，以及写作、编辑审查和提交 科学手稿。这包括针对 AD 和基于 tau 的开发进行差距分析 该计划基于已发表的文献和对 Oligomerix 临床前数据的回顾。这一目标将 包括文献检索、编辑审查和稿件提交。正如国家老龄化研究所 是 AD 研究的主要联邦机构，AD 的 DMT 开发具有最高的相关性 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.