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.

项目摘要 该计划的重点是通过推进我们 将化合物带入临床发展。没有用于AD疾病的药物，并且患病率 广告在全球范围内都在增加。该计划正在进行中，以通过修改疾病的药物来满足这种需求，如果 成功，将对目前有广告的650万美国人产生巨大影响 （预计到2050年为1,270万）及其护理人员，将有助于降低当前成本321亿美元 （到2050年预计将为1.1万亿美元）到我们国家（阿尔茨海默氏症协会2022年阿尔茨海默氏病事实和 数字）。治疗早期广告的关键要求包括安全，高效和具有成本效益的治疗 干预措施。这种小分子类似CNS药物的铅可显着满足这些要求 初步结果。这种高度分化的tau自我关联抑制剂靶向tau在 tau聚合级联的开始。使用体外测定法筛选和优化小分子 选择抑制tau单体形成tau低聚物的分子。体外药理学和 使用小鼠的药代动力学（PK）研究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。方法开发和制造1.61公斤 铅化合物已完成非临床安全研究。 GMP生产2.8千克批次 临床研究完成了，并完成了用于药物开发的预制造研究。 IND被提交（2022年6月1日），首先是人类（FIH）的研究，该研究计划在2022年底或早期开始 2023年。授予的1A期研究是一项双盲，随机，三部分研究，旨在评估 tau自我关联抑制剂的安全性，耐受性和药代动力学，以单次升级剂量，多个 升级剂量和单剂量的健康剂量。这种补充是要涵盖意外的增量 与FDA评论有关我们的IND提交有关的成本 提交。这两年补充的目的如下：目标4。实施和维持剂量暴露 PK模型以确保符合FDA施加的暴露极限。目标5。召集独立的数据安全 监视委员会（DSMB），以确保参与安全。迫切需要支持这些活动并开始 直到PK/PD建模都完成和DSMB，临床活动尽快才能开始 就位。提供此支持的任何延迟都会导致开始该试验的临床活动的延迟。