GMP Production of a Tau Oligomer Inhibitor to Enable Clinical Development for ADRD

Tau 寡聚物抑制剂的 GMP 生产促进 ADRD 的临床开发

基本信息

批准号：
9908941
负责人：
JAMES G. MOE
金额：
$ 122.89万
依托单位：
OLIGOMERIX, INC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908941
关键词：
Acute Alzheimer&apos s Disease Alzheimer&apos s disease related dementia American Biological Assay Caregivers Cause of Death Cellular Assay Chemistry Chronic Chronic Disease Clinical Protocols Clinical Trials Cyclic GMP Dementia Development Disease Doctor of Philosophy Dose Excipients Formulation Funding Funding Opportunities Goals Human In Vitro Kilogram Laboratories Lead Microtubule Stabilization Nerve Degeneration Pathology Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Powder dose form Preparation Preventive Process Production Reporting Research Safety Series Small Business Innovation Research Grant Solubility Tauopathies Techniques Therapeutic Transgenic Mice Translating United States United States National Institutes of Health Work aggregation pathway analytical method capsule clinical development cost efficacy study improved in vitro activity in vitro testing in vivo in vivo Model inhibitor/antagonist method development mouse model novel prevent programs prototype safety study safety testing scale up screening small molecule small molecule inhibitor synaptic function tau Proteins tau aggregation treatment strategy verification and validation

项目摘要

TITLE: GMP Synthesis of a Tau Oligomer Inhibitor to Enable Clinical Development for ADRD PROJECT SUMMARY - SBIR Funding Opportunity: NIA PAS-18-187, "Advancing Research on Alzheimer's Disease (AD) & AD-Related Dementias (ADRD) (R43/R44 Clinical Trial Optional)" The long-term goal of this program is to develop a disease-modifying, small molecule drug for Alzheimer’s disease (AD) and related dementias (ADRD). There is a critical unmet need for a disease modifying drug for AD. Chronic treatment strategies require economically feasible approaches such as small molecule drugs. 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 5.8 million Americans who currently have AD (projected to be 14 million by 2050) and their caregivers, and will help reduce the current cost of $290 billion (projected to be $1.1 trillion by 2050) to our nation. Our small molecule leads target tau self-association into oligomers for neurodegeneration. Tau protein’s normal function is to stabilize microtubules thereby enabling synaptic function. Tau oligomers are the acutely toxic species of tau and their reduction will modify the course of AD. Our in vivo efficacy studies were carried out blindly and independently by Peter Davies, Ph.D., a key opinion leader in the tau targeting field. The lead compound inhibited tau aggregation in transgenic mice expressing human tau (htau), best representing tau aggregation in AD using a preventive paradigm. These results demonstrate that our lead compound reduced self-association of tau and inhibited formation of insoluble tau aggregates. The activity translated from in vitro and cellular assays to an in vivo model of tau aggregation validating our screening approach and showing that targeting oligomer formation can inhibit the entire tau aggregation pathway. Furthermore, preliminary safety testing showed a good profile in terms of MTD, Ames, hERG, 14 day dose range finding study, and safety pharmacology. This application is for the cGMP manufacture of 2 - 3 kilograms of our lead (TO-0582AQ) for use in clinical development. Further, we will develop the IND package for FDA that will be supported by the GLP safety studies that are presently being carried out under a parallel NIH funded program (AG062021). We will also perform pre-formulation work under the proposed program and will qualify activity of API, formulated API and any intermediates using our proprietary in-vitro screening assays. Additional activities to be taken include managing all subcontractors and consultants and responsibility for all reporting requirements to NH for the proposed program. Our collaborators include Edward Cheesman, Ph.D., Chemistry and Manufacturing Controls Consultant who managed our scale up for the non-clinical safety studies, will also help oversee the GMP scale-up of our lead compound for clinical development. Pre-formulation work will be carried out by Rajaram Vaidyanathan, RPh, Ph.D., at Gram Laboratories, Inc. Timothy J. Kachmar, M.S., McCormick LifeSciences, LLC will be our regulatory consultant.

标题：Tau 寡聚物抑制剂的 GMP 合成促进 ADRD 的临床开发项目摘要 - SBIR 资助机会：NIA PAS-18-187，“推进阿尔茨海默病研究疾病 (AD) 和 AD 相关痴呆 (ADRD)（R43/R44 临床试验可选）” 该计划的长期目标是开发一种缓解疾病的小分子药物阿尔茨海默病（AD）和相关痴呆症（ADRD）对一种疾病的需求尚未得到满足。改变 AD 的药物治疗策略需要经济上可行的方法，例如小规模治疗。该计划正在进展中，旨在通过一种疾病修饰药物来满足这一需求，如果成功的话，将对目前患有 AD 的超过 580 万美国人（预计为到 2050 年将有 1,400 万人）及其照顾者，这将有助于减少目前 2,900 亿美元的成本（预计为到 2050 年，我们的小分子将目标 tau 自缔合为寡聚物，为我们的国家提供 1.1 万亿美元。 Tau 蛋白的正常功能是稳定微管，从而实现突触。 Tau 寡聚体是 tau 的剧毒物质，其减少会改变 AD 的进程。我们的体内功效研究是由关键意见 Peter Davies 博士盲目独立进行的该先导化合物可抑制表达转基因小鼠中的 tau 聚集。人类 tau (htau)，最能代表 AD 中使用预防范例的 tau 聚集。证明我们的先导化合物减少了 tau 的自缔合并抑制了不溶性 tau 的形成该活性从体外和细胞测定转化为 tau 聚集的体内模型。验证我们的筛选方法并表明靶向寡聚体形成可以抑制整个 tau 此外，初步安全性测试显示在 MTD、Ames、 hERG、14 天剂量范围寻找研究和安全药理学此应用程序适用于 cGMP。生产 2 - 3 公斤的铅 (TO-0582AQ)，用于临床开发。为 FDA 开发 IND 包，该包将得到目前正在进行的 GLP 安全性研究的支持我们还将在 NIH 资助的并行计划 (AG062021) 下进行预制定工作。拟议的计划，并将使用我们的 API、配制的 API 和任何中间体来限定活性需要采取的其他活动包括管理所有分包商和顾问并负责向 NH 提出的计划的所有报告要求。包括管理我们规模的化学和制造控制顾问 Edward Cheesman 博士进行非临床安全性研究，还将帮助监督我们的临床先导化合物的 GMP 规模扩大预配制工作将由 Gram 的 Rajaram Vaidyanathan 博士进行。 Laboratories, Inc. Timothy J. Kachmar, M.S., McCormick LifeSciences, LLC 将担任我们的监管顾问。