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

项目概要：此R44补充应用程序的重点是开发一个全面的 出版战略，以满足该公司的长期目标，传播其研究成果，以科学 社区拟议的工作旨在为公司制定一个长期的出版计划， 包括在项目期间撰写和出版（2）手稿。AD的患病率是 在全球范围内增加。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。该计划正在取得进展，以满足经济，疾病修饰的需求 药物是稳定的，口服的，可以自我管理。如果成功的话，它将对世界产生巨大的影响。 超过650万美国人目前患有AD（预计到2050年将达到1270万）， 护理人员，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）， 阿尔茨海默病协会2022年阿尔茨海默病的事实和数字（Alzheimer's Association 2022 Alzheimer's Disease Facts and Figures）我们现在已经完成了所有 我们向FDA提交的IND申请的临床前工作，用于我们的首次人体1a期研究，以及我们的IND申请 于2022年6月1日成功提交给FDA（IND # 156701）。这项工作的总结如下：TO-0582 在两种tau蛋白病的小鼠模型（具有人tau蛋白的htau模型）中证实了药理学活性 所有6种异构体最好地代表AD和具有P301 L的JNPL 3小鼠模型中的tau聚集， 突变并代表四重复tau蛋白病），合理的药代动力学特征，最小DDI 对心血管、肺和CNS系统的潜在、无/极小影响，且无遗传毒性。 在28天大鼠和犬GLP毒性研究中观察到相对适度的非不良毒性。无 大鼠和犬28天研究的不良反应水平均为最高试验剂量。因此，TO-0582是一种 用于治疗神经退行性疾病的临床开发的优秀候选者。制造 用于非临床安全性研究（NCSS）和药物预配制工作的2000公斤数量已经完成。 还制备了用于生产制剂OLX-07010的GMP批次。这个目标 补充目标是制定一个全面的出版战略，以完成传播任务 向科学界提供新颖和高度相关的信息，以及撰写、编辑审查和提交 科学手稿。这包括对AD和基于tau的开发进行差距分析 基于已发表的文献和对Oligomerix临床前数据的审查。这一目标将 包括文献检索、编辑审查和提交手稿。作为国家老龄化研究所 作为AD研究的主要联邦机构，开发AD的DMT具有最高的相关性 完成它的使命。

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.