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.

修改后的项目摘要/摘要部分 该申请适用于 AG066384 的 IIb 期 (R44) 更新，标题为“tau 寡聚抑制剂的 GMP 生产，以实现 ADRD 的临床开发”。我们完成了临床前工作并向 FDA 提交了 IND 申请，并准备于 2023 年 1 月开始我们的首次人体 1a 期研究。该申请旨在开展一项为 1b 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估对相关血清和脑脊液生物标志物治疗的反应来寻找疗效/概念验证的早期临床迹象。该计划正在不断进展，旨在通过一种稳定的、口服的、可自行给药的经济的 DMT 来满足 AD 疾病修饰疗法 (DMT) 日益增长的未满足的迫切需求。如果成功，它将对目前患有 AD 的超过 650 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）（阿尔茨海默病协会 2022 年阿尔茨海默病事实和数据）。临床前研究结果表明，TO-0582 证明：在两种 tau 蛋白病小鼠模型中具有药理活性（htau，表达 6 种 CNS 人类 tau 亚型，代表 AD 中的 tau 聚集；JNPL3，表达具有 P301L 突变的 4R tau，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、 对心血管、肺和中枢神经系统没有/最小影响，并且没有遗传毒性。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。有必要进行更高剂量的额外测试，以证明毒性限制剂量，以建立未观察到的不良反应水平（NOAEL），从而使人类的剂量达到足够的水平。用于非临床安全性研究（NCSS）的公斤级生产和药物预配制工作已经完成。该 GMP 批次符合 24 个月稳定性规范，并用于生产 OLX-07010 药品，该产品最近符合 12 个月稳定性测试规范。化合物的方法开发和制造已在 5 公斤规模上得到验证（由 1R44AG077991-01A1 资助）。该提案的目的是合成 10 公斤 TO-0582AA，并使用该材料进行研究，以证明大鼠和狗的毒性限制剂量和 NOAEL。化合物的生产将由 Curia（纽约州奥尔巴尼）进行，毒性研究将由 Charles River Laboratories（俄亥俄州阿什兰）进行。由于国家老龄化研究所是 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。