First in Human Study of a Tau Self-Association Small Molecule Inhibitor in Healthy Volunteers

首次在健康志愿者中进行 Tau 自联小分子抑制剂的人体研究

• 批准号: 10421220
• 负责人: William A. Erhardt
• 金额: $ 158.23万
• 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: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421220
• 关键词: Adult; Adverse event; Alzheimer' s Disease; Alzheimer' s disease patient; American; Benchmarking; Biological Assay; California; Canis familiaris; Caregivers; Cause of Death; Clinical; Clinical Research; Clinical Trials; Development; Disease; Dose; Drug Kinetics; Elderly; Evaluation; Female; Formulation; Frontotemporal Dementia; Future; Goals; Grant; Human; In Vitro; Incidence; Investigational Drugs; Investigational New Drug Application; Kilogram; Lead; Medical; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Pathologic Processes; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Population; Prevalence; Preventive; Progressive Supranuclear Palsy; Randomized; Rattus; Research; Research Design; Safety; Schedule; Single-Blind Study; Special Event; Study Subject; Tauopathies; Therapeutic; Therapeutic Intervention; Therapeutic Studies; United States; Work; advanced disease; appropriate dose; base; clinical development; cohort; cost; cost effective; design; drug development; efficacy study; first-in-human; healthy volunteer; human study; in vitro Assay; in vivo; in vivo evaluation; inhibitor; interest; male; meetings; monomer; mouse model; prevent; programs; response; safety study; small molecule; small molecule inhibitor; success; tau Proteins; tau aggregation; volunteer

PROJECT SUMMARY This program is focused on developing a disease-modifying drug for Alzheimer’s disease (AD) by advancing its small molecule drug OLX-07010 into clinical development. There are no disease-modifying drugs for AD, and the prevalence of AD is increasing worldwide. This program is progressing to fill this need with a disease modifying drug that, if successful, will have a tremendous impact on the more than 6.2 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 $355 billion (projected to be $1.1 trillion by 2050) to our nation (Alzheimer's Association 2021 Alzheimer's Disease Facts and Figures). Key requirements for treating early-stage AD include safe, efficacious, and cost- effective therapeutic interventions. This small molecule, CNS drug-like lead substantially fulfills these requirements based on our preliminary results. This highly differentiated approach targets tau self-association at the beginning of the tau aggregation cascade. Small molecules were screened and optimized using in vitro assays to select molecules that inhibit the formation of tau oligomers from tau monomers. In vitro pharmacology and pharmacokinetic (PK) studies in mice were used to select a lead compound for evaluation of in vivo efficacy. Preventive and therapeutic studies in two mouse models of tauopathy, representing tau aggregation in Alzheimer’s disease (AD) and four-repeat-tau tauopathies, demonstrated proof-of-concept and supported the selection of this compound for further development. 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. A pre-IND meeting written response with FDA is scheduled for July 23, 2021 (PIND Number 156701) to finalize dose selection for the 28-day GLP safety studies in dogs and rats. The Investigational New Drug (IND) application is planned for the first quarter in 2022 to enable the first in human (FIH) studies that are the subject of this application to commence early in the second quarter of 2022. This R01 Phase 1a single-blind, randomized, three-part study is designed to evaluate the safety, tolerability, and pharmacokinetics of the tau self-association inhibitor, in single ascending doses, multiple ascending doses, and a single dose in healthy elderly. The Aim of this application in Year 1 is to demonstrate safety and PK of OLX- 07010 in healthy volunteers after single dosing, and during Year 2 the Aims are to demonstrate safety and PK of OLX-07010 in healthy volunteers after multiple dosing, and to demonstrate safety and PK of OLX-07010 in healthy elderly volunteers after single dosing. These studies will enable the determination of dosing for subsequent proof-of-concept studies in AD and other neurodegenerative diseases.

项目摘要 该计划的重点是通过推进其在阿尔茨海默病（AD）中的作用， 小分子药物OLX-07010进入临床开发。没有针对AD的疾病修饰药物， AD的患病率在世界范围内不断增加。这项计划正在进行，以满足这一需要与疾病 如果成功，将对超过620万美国人产生巨大影响， 目前有AD（预计到2050年将达到1270万）及其护理人员， 我们国家的成本为3550亿美元（预计到2050年将达到1.1万亿美元）（阿尔茨海默氏症协会2021年阿尔茨海默氏症 疾病的事实和数据）。治疗早期AD的关键要求包括安全、有效和成本- 有效的治疗措施。这种小分子CNS药物样先导物基本上满足这些要求。 根据我们的初步结果。这种高度分化的方法靶向tau蛋白的自结合， tau聚集级联的开始。使用体外筛选和优化小分子 选择抑制tau单体形成tau寡聚体的分子的测定。体外药理学 和药代动力学（PK）研究来选择用于评价体内功效的先导化合物。 在两种tau蛋白病小鼠模型中的预防性和治疗性研究，代表了tau蛋白在小鼠中的聚集。 阿尔茨海默病（AD）和四重复tau蛋白病，证明了概念验证，并支持 选择该化合物用于进一步开发。用于非临床安全性的千克数量的生产 研究（NCSS）和药物预配制工作已经完成。还制备了GMP批次用于 生产我们的药物产品OLX-07010。与FDA的IND会议前书面回复定于7月 2021年12月23日（PIND编号156701），以最终确定犬和大鼠28天GLP安全性研究的剂量选择。 研究性新药（IND）申请计划于2022年第一季度进行，以实现第一个人类 (FIH)作为本次申请主题的研究将于2022年第二季度初开始。R01 1a期单盲、随机、三部分研究旨在评估安全性、耐受性和 - tau自缔合抑制剂在单次递增剂量、多次递增剂量中的药代动力学，以及 健康老年人单次给药。第1年申请的目的是证明OLX的安全性和PK- 07010在健康志愿者中单次给药后，以及在第2年期间，目的是证明安全性和PK 研究OLX-07010在健康志愿者中多次给药后的安全性和PK，并证明OLX-07010在 单次给药后的健康老年志愿者。这些研究将能够确定 随后在AD和其他神经退行性疾病中的概念验证研究。