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: 10750078
• 负责人: William A. Erhardt
• 金额: $ 27.27万
• 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/10750078
• 关键词: Adverse event; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; American; Animals; Applications Grants; Award; Benchmarking; Canis familiaris; Cardiopulmonary; Caregivers; Cause of Death; Clinical; Clinical Research; Clinical Trials Data Monitoring Committees; Contract Services; Data; Development; Disease; Dose; Double-Blind Method; Drug Kinetics; Elderly; Electronics; Ensure; Event; Formulation; Funding; Goals; In Vitro; Incidence; Lead; Measures; Metabolism; Mission; Modeling; Monitor; Mus; No-Observed-Adverse-Effect Level; Oral; Parents; Pharmaceutical Preparations; Pharmacology; Phase; Preparation; Prevalence; Preventive; Published Comment; Randomized; Research; Research Design; Safety; Series; Signal Transduction; Special Event; Tauopathies; Technology; Therapeutic Intervention; Therapeutic Studies; Time; Toxicology; United States; United States National Institutes of Health; Update; Urine; Validation; Work; bioprinting; clinical development; cohort; cost; cost effective; dosage; drug development; first-in-human; genotoxicity; healthy volunteer; human data; human study; in vitro Assay; in vivo evaluation; incremental cost; inhibitor; innovation; interest; manufacture; meetings; member; method development; monomer; mouse model; novel; participant safety; pharmacokinetic model; pre-clinical; preclinical study; prevent; programs; research and development; safety study; simulation; small molecule; small molecule inhibitor; success; tau Proteins; tau aggregation; trial design

PROJECT SUMMARY This program is focused on developing a disease-modifying drug for Alzheimer’s disease (AD) by advancing our lead compound 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 6.5 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 $1.1 trillion by 2050) to our nation (Alzheimer's Association 2022 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 significantly fulfills these requirements based on our preliminary results. This highly differentiated tau self-association inhibitor 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. Methods development and manufacture of 1.61 kg of the lead compound was completed for non-clinical safety studies. GMP manufacture of a 2.8 kg batch for initial clinical studies was completed, and pre-formulation studies for development of drug product are completed. The IND was submitted (June 1, 2022) for first in human (FIH) studies that are planned to initiate in late 2022 or early 2023. The awarded Phase 1a study is a double-blind, randomized, three-part study designed to evaluate the safety, tolerability, and pharmacokinetics of the tau self-association inhibitor, in single ascending doses, multiple ascending doses, and single dose in healthy elderly. This Supplement is to cover unanticipated incremental costs related to FDA comments on our IND submission which occurred after the parent application was submitted. The Aims of this two year Supplement are as follows: Aim 4. Implement and maintain a dose exposure PK model to ensure compliance with FDA imposed exposure limits. Aim 5. Convene an independent Data Safety Monitoring Board (DSMB) to ensure participant safety. It is urgent that these activities be supported and started as soon as possible as clinical activities cannot begin until both the PK/PD modeling is complete and the DSMB is in place. Any delay in providing this support will result in a delay to beginning clinical activities for this trial.

项目总结 该计划致力于开发一种治疗阿尔茨海默病(AD)的疾病修改药物，通过推进我们的 将化合物引入临床开发。目前还没有治疗AD的疾病修饰药物，而且AD的患病率 广告在全球范围内都在增加。这项计划正在进行中，以满足这种需求，用一种疾病修饰药物，如果 成功，将对目前患有AD的650多万美国人产生巨大影响 (预计到2050年将达到1270万)和他们的照顾者，并将有助于降低目前3210亿美元的成本 (预计到2050年将达到1.1万亿美元)给我们国家(阿尔茨海默病协会2022年阿尔茨海默病事实和 数字)。治疗早期AD的关键要求包括安全、有效和成本效益高的治疗方法 干预措施。这种小分子的CNS类药物铅极大地满足了这些要求，基于我们的 初步结果。这种高度分化的tau自缔合抑制剂针对tau自缔合 Tau聚集级联的开始。使用体外试验筛选和优化小分子 从tau单体中选择抑制tau低聚物形成的分子。体外药理学和 采用小鼠体内药代动力学(PK)研究方法，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。方法研制1.61公斤重的乳酸菌。 铅化合物完成了非临床安全性研究。首批2.8kgGMP的生产 完成了临床研究，完成了药品开发的处方前研究。这个 IND被提交(2022年6月1日)作为人类(FIH)研究的第一项，计划于2022年底或年初启动 2023年。获奖的1a期研究是一项双盲、随机、三部分的研究，旨在评估 单次递增剂量、多次递增剂量的tau自结合抑制剂的安全性、耐受性和药代动力学 递增剂量，健康老年人单次剂量。本补充资料旨在涵盖意外的增量 与FDA对我们的IND提交的评论相关的成本，这发生在父申请被 已提交。这份两年期补编的目标如下：目标4.实施和维持剂量暴露 PK模式，以确保遵守FDA规定的暴露限制。目标5.召开独立的数据安全会议 监督委员会(DSMB)以确保参与者的安全。当务之急是支持和启动这些活动 在完成PK/PD建模和DSMB之前，尽快开始临床活动 已经就位了。在提供这种支持方面的任何延迟都将导致本试验临床活动的开始延迟。