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

一项为期 26 周的大鼠毒性研究以及 Tau-APP 阿尔茨海默病小鼠模型的功效和生物标志物研究，以支持 1b 期临床研究

• 批准号: 10710197
• 负责人: JAMES G. MOE
• 金额: $ 136.8万
• 依托单位: OLIGOMERIX, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10710197
• 关键词: Acute; Adverse effects; Age Months; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; American; Biochemical; Biological Assay; Biological Markers; Blinded; Brain; Canis familiaris; Cardiopulmonary; Cardiovascular system; Caregivers; Cause of Death; Chronic; Clinical; Clinical Research; Data; Dementia; Development; Diet; Disease; Dose; Double-Blind Method; Drug Kinetics; Electronics; Event; Formulation; Future; Goals; Human; In Vitro; Incidence; Inflammation; Isomerism; Kilogram; Lead; Liquid substance; Lung; Metabolism; Mission; Modeling; Mus; Mutation; National Institute on Aging; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Oral; Outcome; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phosphorylation; Preparation; Prevalence; Preventive; Process; Rattus; Recovery; Research; Safety; Self Administration; Series; Serum; Signal Transduction; Specimen; Sprague-Dawley Rats; System; Tauopathies; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Toxic effect; Toxicology; Transgenic Mice; Translating; Treatment Efficacy; United States; Validation; Work; beta amyloid pathology; bioprinting; clinical candidate; cognitive testing; cost; cost effective; design; efficacy study; first-in-human; genotoxicity; healthy volunteer; in vivo; innovation; manufacture; manufacturing scale-up; method development; mouse model; novel; pharmacokinetic characteristic; pharmacologic; pre-clinical; preclinical development; preclinical study; prevent; process improvement; programs; research and development; safety study; small molecule; small molecule inhibitor; tau Proteins; tau aggregation; therapy development; treatment response

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.

项目摘要：此R44应用集中于为1B期临床研究的准备 通过评估对相关系列的治疗的响应，效率/概念证明的早期临床迹象 在对阿尔茨海默氏病患者的双盲研究中，CSF生物标志物。拟议的工作是 旨在支持对生物标志物产生影响的长期剂量。广告的流行是 在全球范围内增加。迫切需要修改具有成本效益的AD药物的疾病 易于管理。该计划正在逐步满足经济，疾病改良的需求 稳定，口服的药物可以自我管理。如果成功，它将对 目前拥有广告的650万美国人（预计到2050年为1,270万）及其 护理人员，将有助于减少当前成本3210亿美元（预计到2050年为1万亿美元） 国家（阿尔茨海默氏症协会2022年阿尔茨海默氏病的事实和数字）。我们现在已经完成了 我们在FDA应用于我们的第一阶段1A研究的临床前工作。这项工作的摘要 以下内容：TO-0582在两种小鼠tauopathy模型（HTAU模型）中展示了药理活性 拥有所有6种异构体的人tau最能代表AD中的Tau聚集，在JNPL3小鼠模型中 具有P301L突变，代表四重的Tauopathies），合理的药代动力学特征， 最小的DDI潜力，对心血管，肺和CNS系统的缺乏/最小影响，并且缺乏 遗传毒性。在28天的大鼠和狗GLP毒性研究中观察到了相对适度的非不良毒性。 大鼠和狗28天研究的无不良反应水平是最高剂量测试的。那， 0582是治疗神经退行性疾病的临床发育的绝佳候选者。 用于非临床安全研究（NCSS）和药物预先制定工作的千克量具有 我们完成了。还准备了GMP批次用于制造我们的药物OLX-07010。我们是 为我们的1A期研究准备我们的电子IND应用程序，该研究将于4月中旬提交给FDA 预计将在2022年6月开始进行最初的人类研究。拟议计划的目的是：AIM 1 在为期四周的恢复期（GLP）的大鼠中，进行26周的口腔毒性研究（GLP）。这 包括扩大TO-0582至5公斤水平的制造。目标2：进行治疗疗法 TAPP小鼠的效率研究；和目标3：进行急性治疗效率研究TAPP小鼠。 第二和第三目的将评估可以转化为计划的1B临床广告研究的生物标志物 并显示具有Tau和淀粉样β病理学，急性和 慢性剂量研究将在TAU-APP（TAPP）小鼠中进行，该小鼠将支持临床的过渡 从健康的志愿者到患者的工作。由于国家老化研究所是主要的联邦机构 广告研究是DMT的AD开发，其使命具有最大的意义。