A 26-week rat toxicity study and efficacy and biomarker studies in Tau-APP Alzheimer's mouse model to support a Phase 1b clinical study

项目摘要：此R44应用程序的重点是为1b期临床研究做准备 通过评估相关血清的治疗反应，获得疗效/概念验证的早期临床体征 和脑脊液生物标记物在阿尔茨海默病患者的双盲研究中。建议的工作是 旨在支持对生物标志物产生影响所需的更长时间的剂量。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 为我们的第一个人类1a期研究向FDA申请IND的临床前工作。这项工作的总结 以下：TO-0582在两种紧张症小鼠模型(htau模型， 在AD和JNPL3小鼠模型中，人tau具有所有6个异构体，最能代表tau聚集 具有P301L突变并代表四重复转位病)，合理的药代动力学特征， DDI潜力最小，对心血管、肺和中枢系统缺乏/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。 在大鼠和狗的28天研究中，没有不良反应的水平是测试的最高剂量。因此，要- 0582是治疗神经退行性疾病临床开发的极佳候选药物。 用于非临床安全性研究(NCS)和药物配方前工作的千克数量的制造 已经完成了。我们还为我们的药品OLX-07010的生产准备了一批GMP。我们是 为我们的1a阶段研究准备电子IND申请，该研究将于2022年4月中旬提交给FDA 预计首个人体研究将于2022年6月开始。拟议方案的目标是：目标1 对恢复期为4周的大鼠进行为期26周的经口毒性研究(GLP)。这 包括扩大TO-0582至5公斤级别的制造。目标2：进行治疗性治疗 在TAPP小鼠中的疗效研究；以及目标3：进行TAPP小鼠的急性疗效研究。这个 第二和第三个目标将评估可能转化为计划中的1b期临床AD研究的生物标记物 并在tau和淀粉样β蛋白病理的小鼠模型上显示该化合物的疗效，急性和 将在tau-app(TAPP)小鼠身上进行慢性给药研究，这将支持临床过渡 从健康志愿者到患者。因为国家老龄问题研究所是联邦政府 AD研究，即为AD开发DMT，与其使命具有最高的相关性。

PROJECT SUMMARY: This R44 application is focused on preparations for a phase 1b clinical study to look for early clinical signs of efficacy/proof-of-concept by evaluating the response to treatment of relevant serum and CSF biomarkers in a double blinded study of patients with Alzheimer’s Disease. The proposed work is designed to support longer term dosing required to see an effect on biomarkers. 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. 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. We are preparing our electronic IND application for our phase 1a study that will be submitted to FDA by mid-April 2022 and anticipate first-in-human studies will begin in June of 2022. The Aims of the proposed program are: Aim 1 Perform 26-weeks oral toxicity study (GLP) in Rats with a four-week recovery period (GLP). This includes scaling up the manufacture of TO-0582 to 5 kg level. Aim 2: Conduct a therapeutic therapeutic efficacy study in TAPP mice; and Aim 3: Conduct an acute therapeutic efficacy study TAPP mice. The second and third Aims will evaluate biomarkers that could translate into the planned Phase 1b clinical AD study and to show efficacy of the compound in a mouse model with tau and amyloid beta pathology, acute and chronic dosing studies will be performed in the tau-APP (TAPP) mice which will support transition of clinical work from healthy volunteers to patients. 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.