GMP Production of a Tau Oligomer Inhibitor to Enable Clinical Development forADRD

Tau 寡聚物抑制剂的 GMP 生产促进 ADRD 的临床开发

• 批准号: 10759200
• 负责人: JAMES G. MOE
• 金额: $ 149.63万
• 依托单位: OLIGOMERIX, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759200
• 关键词: Adverse effects; Adverse event; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; American; Animals; Behavioral; Biological Markers; Canis familiaris; Cardiovascular system; Caregivers; Cause of Death; Clinical; Clinical Research; Data; Development; Disease; Dose; Dose Limiting; Double-Blind Method; Formulation; Funding; Goals; Human; Humidity; In complete remission; Incidence; Kilogram; Laboratories; Lung; Mission; Modeling; Mutation; National Institute on Aging; Neurofibrillary Tangles; No-Observed-Adverse-Effect Level; Oral; Pharmaceutical Preparations; Phase; Prevalence; Preventive; Process; Production; Protein Isoforms; Rattus; Reporting; Research; Research Design; Self Administration; Series; Serum; Specific qualifier value; System; Tauopathies; Technology; Test Result; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Toxic effect; Toxicology; United States; Work; clinical development; cohort; cost; cost effective; design; first-in-human; genotoxicity; healthy volunteer; human study; inhibitor; innovation; manufacture; meetings; method development; mouse model; novel; pharmacokinetic characteristic; pharmacologic; pre-clinical; preclinical study; prevent; programs; public health relevance; research and development; safety study; small molecule; small molecule inhibitor; stability testing; tau Proteins; tau aggregation; treatment response

Modified Project Summary/Abstract Section This application is for a Phase IIb (R44) renewal of AG066384 titled “GMP production of a tau oligomer inhibitor to enable clinical development for ADRD”. We completed the preclinical work and submitted our IND application to FDA and are ready to begin our first-in-human phase 1a study in January 2023. This application is to perform a study needed to prepare for a phase 1b clinical study designed 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 (AD). This program is progressing to fill the urgent, growing unmet need for disease modifying therapeutics (DMT) for AD with an economical, DMT that is stable, oral, and that 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). Results of the preclinical studies have shown that TO-0582 demonstrated: pharmacologic activity in two mouse models of tauopathy (htau, expressing the 6 CNS human tau isoforms representing tau aggregation in AD; JNPL3, that expresses 4R tau with the P301L mutation that 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. Additional testing at higher doses is necessary to demonstrate toxicity limiting dosing to establish a No Observed Adverse Effect Level (NOAEL) to enable dosing at sufficient levels in humans. Manufacture of kilogram quantities for non-clinical safety studies (NCSS) and drug pre-formulation work has been completed. The GMP batch met specifications for 24-month stability and was used to manufacture drug product OLX-07010 that has recently met specifications for 12-month stability testing. Methods development and manufacture of compound has been demonstrated at a 5 Kg scale (funded by 1R44AG077991-01A1). The Aims of this proposal are to synthesize 10 Kg of TO-0582AA and to use this material to perform studies to demonstrate toxicity limiting doses and NOAELs in rats and dogs. Manufacture of compound will be performed by Curia (Albany, NY), and the toxicity studies will be performed by Charles River Laboratories (Ashland, OH). 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.

修改项目摘要/摘要部分 本申请是AG 066384的IIb期（R44）更新，标题为“GMP生产tau寡聚体抑制剂以实现ADRD的临床开发”。我们已完成临床前工作并向FDA提交IND申请，并准备于二零二三年一月开始首次人体1a期研究。本申请旨在进行一项为Ib期临床研究做准备所需的研究，该研究旨在通过在阿尔茨海默病（AD）患者的双盲研究中评价相关血清和CSF生物标志物对治疗的反应来寻找疗效/概念验证的早期临床体征。该计划正在进行，以满足迫切的，日益增长的未满足的需求，疾病修饰治疗（DMT）的AD与经济，DMT是稳定的，口服，并可以自我管理。如果成功，它将对目前患有AD的650多万美国人（预计到2050年将达到1270万）及其护理人员产生巨大影响，并将有助于减少我们国家目前3210亿美元的成本（预计到2050年将达到1万亿美元）。临床前研究的结果表明，TO-0582在两种tau蛋白病小鼠模型中表现出药理学活性（htau，表达代表AD中tau聚集的6种CNS人tau同种型; JNPL 3，其表达具有代表四重复tau蛋白病的P301 L突变的4 R tau），合理的药代动力学特征，最小DDI潜力，对心血管缺乏/最小影响，肺和中枢神经系统，以及缺乏遗传毒性。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。有必要在较高剂量下进行额外试验，以证明毒性限制剂量，从而确定无明显不良作用水平（NOAEL），从而能够在人体中以足够的水平给药。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已经完成。该GMP批次符合24个月稳定性的质量标准，并用于生产制剂OLX-07010，该制剂最近符合12个月稳定性检测的质量标准。化合物的方法开发和生产已在5 Kg规模下得到证实（由1 R44 AG 077991 - 01 A1资助）。本提案的目的是合成10 Kg TO-0582 AA，并使用该材料进行研究，以证明大鼠和犬的毒性限制剂量和NOAEL。化合物的生产将由Curia（奥尔巴尼，NY）进行，毒性研究将由Charles River Laboratories（阿什兰，OH）进行。由于国家老龄研究所是AD研究的主要联邦机构，因此AD DMT的开发与其使命具有最高的相关性。