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

标题：GMP合成一种Tau低聚物抑制剂，使ADRD的临床开发成为可能 项目摘要-SBIR资助机会：NIA PAS-18-187，“推进阿尔茨海默氏症研究 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治疗疾病的小分子药物 阿尔茨海默病(AD)和相关痴呆(ADRD)。对某种疾病有一种严重的未得到满足的需求 修改治疗AD的药物。慢性治疗策略需要经济上可行的方法，如Small 分子药物。这个项目正在用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580多万美国人产生巨大影响(预计 到2050年将达到1400万美元)及其照顾者，并将有助于降低目前2900亿美元的成本(预计 到2050年，为我们的国家提供1.1万亿美元)。我们的小分子将靶标tau自缔合成低聚物，用于 神经退行性变。Tau蛋白的正常功能是稳定微管，从而使突触 功能。Tau寡聚体是tau的剧毒物种，它们的还原将改变AD的进程。 我们的体内疗效研究是由彼得·戴维斯博士盲目独立进行的，他是一位关键观点 在tau靶标领域处于领先地位。铅化合物抑制tau基因在转基因小鼠中的聚集 人类tau(Htau)，最好地代表了使用预防性范例的AD中的tau聚集。这些结果 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。 集合体。活性从体外和细胞检测转化为体内tau聚集模型 验证了我们的筛选方法，并表明靶向低聚物的形成可以抑制整个tau 聚集途径。此外，初步安全测试显示，MTD，Ames， HERG，14天剂量范围发现研究和安全药理学。这个应用程序是针对cGMP的 生产2-3公斤的铅(TO-0582AQ)，用于临床开发。此外，我们还将 为FDA开发IND包，这将得到目前正在进行的GLP安全研究的支持 在美国国立卫生研究院资助的并行项目(AG062021)下进行。我们亦会在下列计划下进行制订前的工作 建议的计划，并将资格的原料药，制定的原料药和任何中间体使用我们的 专有的体外筛选试验。将采取的其他活动包括管理所有分包商和 顾问并负责向NH汇报所提议项目的所有要求。我们的合作者 包括管理我们规模的化学和制造控制顾问Edward Cheesman博士 为非临床安全性研究做准备，也将有助于监督我们临床用先导化合物的GMP放大 发展。配方前工作将由RPh博士Rajaram Vaidyanathan在Gram进行 实验室，Inc.Timothy J.Kachmar，M.S.，McCormick LifeSciences，LLC将担任我们的监管顾问。

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.