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.

修改的项目摘要/摘要部分 该应用是针对AG066384的IIB期（R44）续订，标题为“ GMP生产Tau低聚物抑制剂，以实现ADRD的临床开发”。 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).该计划正在进行中，以填补对疾病修饰治疗（DMT）的紧急，未满足的需求，该AD具有经济的，稳定，口头的经济性DMT，并且可以自我管理。如果成功，它将对超过650万的影响产生巨大影响。目前拥有广告的美国人（预计到2050年为1,270万）及其护理人员，并将有助于降低我们国家的当前成本3210亿美元（预计到2050年为1万亿美元）（阿尔茨海默氏症协会2022年，阿尔茨海默氏病的事实和图）。 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,对心血管，肺和中枢神经系统系统的缺乏/最小影响，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。需要进行较高剂量的其他测试以证明毒性限制剂量以建立未观察到的不良效应水平（NOAEL）以使人类足够水平的给药能力。非临床安全研究（NCSS）和药物预先制定工作的千克量已经完成。 GMP批处理满足了24个月稳定性的规格，并用于制造药物OLX-07010，该产品最近符合12个月稳定性测试的规格。方法的开发和制造已经以5公斤的比例证明（由1R44AG077991-01A1资助）。该提案的目的是合成10千克的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。化合物的制造将由库里亚（纽约州奥尔巴尼）进行，毒性研究将由查尔斯河实验室（俄亥俄州阿什兰）进行。由于国家老化研究所是AD研究的主要联邦机构，因此DMT的AD开发与其任务的相关性最高。