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: 10673633
• 负责人: William A. Erhardt
• 金额: $ 203.96万
• 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/10673633
• 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; Phase; Population; Prevalence; Preventive; Progressive Supranuclear Palsy; Randomized; Rattus; Research; Safety; Schedule; Single-Blind Study; Special Event; Study Subject; Tauopathies; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Toxicology; United States; Work; Writing; appropriate dose; 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; manufacture; monomer; mouse model; pharmacologic; pre-Investigational New Drug meeting; prevent; programs; response; safety assessment; 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疾病改良药物来为阿尔茨海默氏病（AD）开发 小分子药物OLX-07010用于临床发育。没有用于AD疾病的药物，并且 广告的普遍性在全球范围内增加。该计划正在进行中，以满足疾病的需求 修改药物，如果成功，将对超过620万美国人产生巨大影响 目前有广告（预计到2050年为1,270万）及其护理人员，将有助于减少当前 到我们国家的成本为3550亿美元（预计到2050年为1.1万亿美元）（阿尔茨海默氏症协会2021年阿尔茨海默氏症 疾病事实和数字）。治疗早期广告的关键要求包括安全，高效和成本 - 有效的治疗干预措施。这个小分子类似CNS药物的铅基本上实现了这些 根据我们的初步结果的要求。这种高度差异化的方法针对tau自我关联 tau聚合级联的开始。使用体外筛选和优化小分子 选择抑制tau单体形成tau低聚物的分子的测定。体外药理学 小鼠中的药代动力学（PK）研究用于选择铅化合物以评估体内效率。 在两种小鼠tauopathy模型中的预防和治疗研究，代表tau聚集 阿尔茨海默氏病（AD）和四重 - 陶二氏病，证明了概念证明并支持了 选择该化合物以进行进一步开发。制造非临床安全的千克数量 研究（NCSS）和药物预先制定工作已经完成。还为GMP批量准备了 我们的药品OLX-07010的生产。原定于FDA的预定会议的书面答复定于7月 23，2021（Pind Number 156701）为狗和大鼠的28天GLP安全研究完成剂量选择。 计划在2022年第一季度进行调查新药（IND）申请，以使人类第一 （FIH）研究是该应用于2022年第二季度开始的该申请的主题。此R01 1A期单盲，随机，三部分研究旨在评估安全性，耐受性和 tau自我关联抑制剂的药代动力学，单次升级剂量，多种升剂剂量和 较健康的健康剂量。该应用在第1年的目的是证明OLX-的安全性和PK 单次剂量后，健康志愿者的07010，在第2年期间，目的是证明安全和PK 多次剂量后，健康志愿者的OLX-07010的of of of Healthy志愿者，并证明OLX-07010的安全性和PK 单次给药后健康的志愿者。这些研究将能够确定给药 随后在AD和其他神经退行性疾病中进行概念验证研究。