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

项目总结 该计划的重点是开发一种治疗阿尔茨海默病(AD)的疾病修改药物，通过促进其 小分子药物OLX-07010进入临床开发。目前还没有治疗阿尔茨海默病的药物， 阿尔茨海默病在世界范围内的流行程度正在上升。这项计划正在取得进展，以满足这种疾病的需求 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AD(预计到2050年将达到1270万)和他们的照顾者，并将有助于减少目前的 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)(阿尔茨海默病协会，2021年阿尔茨海默病 疾病事实和数字)。治疗早期AD的关键要求包括安全、有效和成本- 有效的治疗干预。这种小分子的中枢神经系统类药物铅基本上实现了这些 根据我们的初步结果提出要求。这种高度差异化的方法以tau自关联为目标 Tau聚集级联的开始。在体外筛选和优化小分子 从tau单体中选择抑制tau低聚物形成的分子的分析。体外药理学 并通过小鼠体内药代动力学(PK)研究，选择一种先导化合物进行体内药效评价。 两种Tau病小鼠模型的预防和治疗研究，表现为Tau在 阿尔茨海默病(AD)和四重陶氏症，证明了概念的验证，并支持 选择该化合物进行进一步开发。用于非临床安全的千克量的制造 研究(NCS)和药物配方前工作已经完成。还准备了一批GMP用于 生产我们的药品OLX-07010。IND前会议与FDA的书面回应定于7月进行 23,2021年(PIND编号156701)，最终确定为期28天的狗和大鼠普洛斯安全性研究的剂量选择。 研究新药(IND)的申请计划于2022年第一季度进行，以实现人类首个 (FIH)作为本申请主题的研究将于2022年第二季度初开始。本R01 第1阶段：一项单盲、随机、三部分的研究，旨在评估该药的安全性、耐受性和 Tau自结合抑制剂在单次递增剂量、多次递增剂量和 健康老年人单次服用。此应用程序在第一年的目的是演示OLX的安全性和PK- 07010的健康志愿者在单次给药后，在第二年的目的是证明安全性和PK 健康志愿者多次给药后口服OLX-07010，并证明其安全性和PK。 健康老年志愿者单次给药。这些研究将使确定药物的剂量成为可能 随后对阿尔茨海默病和其他神经退行性疾病的概念验证研究。

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.