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

• 批准号: 10025563
• 负责人: JAMES G. MOE
• 金额: $ 95.45万
• 依托单位: OLIGOMERIX, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025563
• 关键词: Acute; Alzheimer' s Disease; Alzheimer' 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

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：GMP合成TAU低聚物抑制剂以实现ADRD的临床开发 项目摘要 - SBIR资助机会：NIA PAS-18-187，“促进阿尔茨海默氏症的研究 疾病（AD）和与AD相关的痴呆症（ADRD）（R43/R44临床试验可选）” 该计划的长期目标是开发一种改良疾病的小分子药物 阿尔茨海默氏病（AD）和相关痴呆症（ADRD）。对疾病有关键的未满足需求 修饰AD的药物。长期治疗策略需要经济上可行的方法，例如小 分子药物。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580万美国人产生巨大影响（预计是） 到2050年）及其护理人员，将有助于降低当前成本2900亿美元（预计为 到2050年，到我们的国家为1.1万亿美元。我们的小分子将目标tau自我关联引导到低聚物中 神经变性。 tau蛋白的正常功能是稳定微管，从而实现突触 功能。 Tau低聚物是Tau的急性毒性，其还原将改变AD的过程。 我们的体内效率研究是由彼得·戴维斯（Peter Davies）博士盲目而独立地进行的，这是一个关键人物 TAU目标领域的领导者。铅化合物抑制了表达的转基因小鼠的tau聚集 人tau（HTAU），使用预防范式最好代表AD中的Tau聚集。这些结果 证明我们的铅化合物减少了tau的自我关联并抑制了不溶性tau的形成 聚合。该活性从体外和细胞分析转化为tau聚集的体内模型 验证我们的筛选方法并表明靶向寡聚形成可以抑制整个TAU 聚合途径。此外，初步安全测试在MTD，Ames， HERG，14天的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。此外，我们会的 开发FDA的IND软件包，该包将由GLP安全研究支持，目前正在 根据平行的NIH资助计划（AG062021）进行。我们还将在 拟议的计划，并将使用我们 专有体外筛选测定法。要采取的其他活动包括管理所有分包商和 顾问和对NH的所有报告要求的责任。我们的合作者 包括Edward Cheesman博士，化学和制造控件顾问，他们管理了我们的规模 进行非临床安全研究，还将有助于监督我们的铅化合物的GMP缩放量表 发展。 Rajaram Vaidyanathan，RPH，Ph.D。将在Gram上进行预制造工作 Laboratories，Inc。M.S. Timothy J. Kachmar，McCormick Lifesciences，LLC将是我们的监管顾问。