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

修改后的项目摘要/摘要部分 本申请是AG066384的第IIb阶段(R44)的续展，标题为“生产tau齐聚物抑制剂以实现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，并准备在2023年1月开始我们的第一个人类1a阶段研究。这项应用是为了进行一项为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相关血清和脑脊液生物标记物的治疗反应，寻找疗效/概念验证的早期临床迹象。这项计划正在进行中，以满足AD疾病修改疗法(DMT)日益增长的迫切需求，提供一种经济的、稳定的、口服的、可以自我管理的DMT。如果成功，它将对目前超过650万患有阿尔茨海默病的美国人(预计到2050年将达到1270万人)和他们的照顾者产生巨大影响，并将有助于减少我们国家目前3210亿美元(预计到2050年将达到1万亿美元)的成本(阿尔茨海默氏症协会2022年阿尔茨海默病事实和数据)。临床前研究结果表明，TO-0582在两种tau病小鼠模型中具有药理活性(htau表达6种CNS人tau亚型在AD中聚集；JNPL3表达4R tau与P301L突变代表四重复tauopathy)、合理的药代动力学特征、最小的DDI电位、对心血管、肺和中枢系统缺乏/极小的影响，以及缺乏遗传毒性。在28天的大鼠和狗的GLP毒性研究中，观察到相对温和的非不良毒性。在大鼠和狗的28天研究中，没有不良反应的水平是测试的最高剂量。在更高剂量下进行额外的测试是必要的，以证明毒性限制剂量，以建立没有观察到的不良反应水平(NOAEL)，以便能够在人体内以足够的水平进行剂量。用于非临床安全性研究(NCS)和药物配方前工作的千克数量的制造已经完成。GMP批次达到了24个月稳定性的规格，并用于生产最近达到12个月稳定性测试规格的药品OLX-07010。方法化合物的开发和制造已在5公斤的规模上进行了论证(由1R44AG077991-01A1资助)。这项提议的目的是合成10公斤的TO-0582AA，并使用这种材料进行研究，以证明对大鼠和狗的毒性限量和NOAELs。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。由于国家老龄问题研究所是AD研究的主要联邦机构，开发AD的DMT对其使命具有最高的相关性。

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.