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: 10603544
• 负责人: JAMES G. MOE
• 金额: $ 112.5万
• 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/10603544
• 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; 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; manufacturing scale-up; method development; mouse model; novel; pharmacokinetic characteristic; pre-clinical; preclinical development; preclinical study; prevent; 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：该 R44 申请的重点是 1b 期临床研究的准备工作 通过评估相关血清治疗的反应来获得疗效/概念验证的早期临床症状 和脑脊液生物标志物在阿尔茨海默氏病患者的双盲研究中的研究。 旨在支持需​​要长期给药以观察对生物标志物的影响 AD 的患病率是。 全球范围内仍然迫切需要具有成本效益的 AD 疾病缓解药物。 该计划正在不断发展，以满足经济、疾病缓解的需求。 稳定的、口服的、可以自行给药的药物如果成功的话，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） （阿尔茨海默病协会 2022 年阿尔茨海默病事实和数据）我们现已完成所有内容。 我们向 FDA 申请首次人体 1a 期研究的 IND 申请的临床前工作 这项工作的摘要。 如下：TO-0582 在两种 tau 蛋白病小鼠模型（tau 模型 人类 tau 蛋白具有所有 6 种异构体，最能代表 AD 和 JNPL3 小鼠模型中的 tau 蛋白聚集 具有 P301L 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 潜力，缺乏/对心血管、肺和中枢神经系统的影响最小，以及缺乏 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。 大鼠和狗 28 天研究的无副作用水平是测试的最高剂量。 0582是神经退行性疾病治疗临床开发的优秀候选药物。 用于非临床安全性研究 (NCSS) 和药物预配制工作的公斤量生产已 我们还准备了 GMP 批次的药品 OLX-07010 的生产。 为 1a 期研究准备电子 IND 申请，该申请将于 2022 年 4 月中旬提交给 FDA 预计首次人体研究将于 2022 年 6 月开始。拟议计划的目标是： 目标 1 在大鼠中进行 26 周的口服毒性研究 (GLP)，并有 4 周的恢复期 (GLP)。 包括将 TO-0582 的生产规模扩大到 5 千克水平 目标 2：进行治疗性治疗。 TAPP 小鼠的疗效研究；目标 3：进行 TAPP 小鼠的急性治疗效果研究。 第二个和第三个目标将评估可转化为计划中的 1b 期临床 AD 研究的生物标志物 并展示该化合物在具有 tau 蛋白和 β 淀粉样蛋白病理学、急性和 慢性剂量研究将在 tau-APP (TAPP) 小鼠中进行，这将支持临床过渡 国家老龄化研究所是负责处理从健康志愿者到患者的主要联邦机构。 AD 研究，即针对 AD 的 DMT 的开发，与其使命具有最高的相关性。