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

项目概述：该R44申请的重点是1b期临床研究的准备工作， 通过评价对相关血清治疗的反应，获得疗效/概念验证的早期临床体征 和CSF生物标志物在阿尔茨海默病患者的双盲研究中的作用。拟议的工作是 旨在支持观察对生物标志物的影响所需的长期给药。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 临床前工作，我们的IND申请FDA为我们的第一个在人体1a期研究。这项工作的总结 TO-0582在两种tau蛋白病小鼠模型（htau模型， 在AD和JNPL 3小鼠模型中， 具有P301 L突变并代表四重复tau蛋白病），合理的药代动力学特征， DDI可能性极小，对心血管、肺和CNS系统无影响/影响极小， 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。 大鼠和犬28天研究的无不良作用水平均为最高试验剂量。因此，要- 0582是用于治疗神经退行性疾病的临床开发的优秀候选物。 用于非临床安全性研究（NCSS）和药物预配制工作的千克数量的生产， 完成了还制备了用于生产制剂OLX-07010的GMP批次。我们 为我们的1a期研究准备电子IND申请，该研究将于2022年4月中旬提交给FDA 并预计首次人体研究将于2022年6月开始。拟议方案的目标是：目标1 在大鼠中进行26周经口给药毒性研究（GLP），含4周恢复期（GLP）。这 包括将TO-0582的生产规模扩大到5 kg水平。目标2：进行治疗性治疗 目标3：进行TAPP小鼠急性治疗功效研究。的 第二个和第三个目标将评估可能转化为计划的1b期临床AD研究的生物标志物 并显示该化合物在具有tau和淀粉样蛋白β病理学的小鼠模型中的功效， 将在tau-APP（TAPP）小鼠中进行慢性给药研究，这将支持临床试验的过渡。 从健康志愿者到患者。由于国家老龄化研究所是主要的联邦机构， AD研究，即AD DMT的开发，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.