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.

项目概要 该项目的重点是通过推进其治疗阿尔茨海默病（AD）的疾病缓解药物 小分子药物OLX-07010进入临床开发。没有针对 AD 的疾病缓解药物，并且 AD 的患病率在全世界范围内不断增加。该计划正在进展中，以满足疾病的这一需求 如果成功的话，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）及其照顾者，这将有助于减少当前的AD 给我们国家造成 3550 亿美元的损失（预计到 2050 年将达到 1.1 万亿美元）（阿尔茨海默病协会 2021 年阿尔茨海默病 疾病事实和数据）。治疗早期 AD 的关键要求包括安全、有效和成本低廉。 有效的治疗干预。这种小分子中枢神经系统药物样铅基本上满足了这些要求 根据我们的初步结果提出要求。这种高度差异化的方法针对 tau 自关联 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 寡聚体的分子的分析。体外药理学 小鼠体内药代动力学（PK）研究用于选择先导化合物来评估体内功效。 两种 tau 蛋白病小鼠模型的预防和治疗研究，代表了 tau 蛋白聚集 阿尔茨海默病 (AD) 和四重复 tau 蛋白病，经过概念验证并支持 选择该化合物进行进一步开发。为非临床安全而进行公斤级生产 研究（NCSS）和药物预配制工作已经完成。还准备了 GMP 批次 生产我们的药品 OLX-07010。计划于 7 月向 FDA 提交 IND 前会议书面答复 2021 年 2 月 23 日（PIND 号 156701）最终确定针对狗和大鼠进行的 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，以实现首次人体试验 (FIH) 作为本申请主题的研究将于 2022 年第二季度初开始。此 R01 1a 期单盲、随机、三部分研究旨在评估安全性、耐受性和 单次递增剂量、多次递增剂量的 tau 自缔合抑制剂的药代动力学，以及 健康老年人单剂量。第一年该申请的目的是证明 OLX-的安全性和 PK 07010 在单次给药后的健康志愿者中，第 2 年的目标是证明安全性和 PK 多次给药后 OLX-07010 在健康志愿者中的变化，并证明 OLX-07010 在健康志愿者中的安全性和 PK 健康老年志愿者单次给药后。这些研究将有助于确定剂量 随后针对 AD 和其他神经退行性疾病的概念验证研究。