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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos 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

项目摘要

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.

项目概要该计划的重点是通过推进我们的研究，开发一种治疗阿尔茨海默病 (AD) 的疾病缓解药物。目前尚无针对 AD 的疾病缓解药物，且 AD 的患病率较高。 AD 正在全球范围内不断增加，该计划正在不断发展，以期通过一种疾病缓解药物来满足这一需求。成功的话，将对目前患有 AD 的超过 650 万美国人产生巨大影响（预计到 2050 年将达到 1270 万人）及其照顾者，并将有助于减少当前 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治疗早期 AD 的关键要求包括安全、有效和具有成本效益的治疗。根据我们的研究，这种小分子中枢神经系统药物样药物显着满足了这些要求。初步结果表明，这种高度分化的 tau 自缔合抑制剂以 tau 自缔合为目标。使用体外测定筛选和优化 tau 聚集级联的开始。选择抑制 tau 单体形成 tau 寡聚物的分子。小鼠药代动力学（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) 和四次重复 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和生产 1.61 千克。已完成 2.8 公斤批次的先导化合物的非临床安全性研究。临床研究已完成，药品开发的制剂前研究也已完成。首次人体 (FIH) 研究已提交 IND（2022 年 6 月 1 日），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、三部分研究，旨在评估 tau 自缔合抑制剂的安全性、耐受性和药代动力学，单次递增剂量、多次递增剂量和健康老年人的单剂量本补充品旨在涵盖意外的增量。与 FDA 对我们的 IND 提交的评论相关的费用，该评论是在母申请获得批准后发生的提交的两年期补充文件的目标如下：目标 4. 实施并维持剂量暴露。 PK 模型确保符合 FDA 规定的暴露限制。目标 5：召集独立的数据安全委员会。监测委员会（DSMB）确保参与者的安全迫切需要支持和启动这些活动。尽快开始，直到 PK/PD 建模完成且 DSMB 完成后才能开始临床活动提供此支持的任何延迟都将导致该试验的临床活动开始延迟。