Development and Commercialization of a Tau Oligomer Inhibitor for AD/RD

标题：用于AD/RD的Tau寡聚体抑制剂的开发和商业化 项目摘要- SBIR/STTR商业化准备试点（CRP）计划（PAR-19-333） 该项目的长期目标是开发一种治疗阿尔茨海默氏症的疾病修饰小分子药物 疾病（AD）和相关痴呆（ADRD）。存在对用于以下的疾病修饰药物的关键未满足的需求： AD.慢性治疗策略需要经济上可行的方法，如小分子药物。我们 小分子导致靶tau自结合成用于神经变性寡聚体， 区别于竞争。Tau寡聚体是Tau蛋白的急性毒性种类， 减少将改变AD的进程。我们的体内疗效研究是盲法和独立进行的 作者：Peter Davies，Ph.D.在tau蛋白靶向领域的关键意见领袖在转基因小鼠的预防性研究中， 先导化合物在表达人tau（HTU）转基因小鼠中抑制tau聚集， 代表AD中的tau聚集，或JNPL 3小鼠模型中的聚集倾向突变的tau（P301 L）。 遗传性tau蛋白病这些结果表明，我们的先导化合物减少了tau蛋白的自缔合， 抑制不溶性tau聚集体的形成。活性从体外和细胞试验转化为体内试验， tau聚集的体内模型验证了我们的筛选方法，并显示靶向寡聚体形成 可以抑制整个tau聚集途径。体外药理学试验（非GLP），如艾姆斯、hERG， 和DiscoverX Safety 47 ™面板显示出良好的安全性，并且该化合物在人体中高度稳定 肝微粒体稳定性研究。大鼠体内安全性试验（非GLP）显示最大耐受剂量 (MTD)在一项为期14天的剂量范围探索研究中，在400 mg/kg剂量下未发现不良反应。 将对稳定的， 所配制的化合物的游离碱多晶型物。我们使用的电极导线的cGMP生产和配方 临床开发也在进行中（批准编号AG 066384）。此应用程序用于商业化 IND申请所需的活动和技术及咨询工作。中不存在重叠 用我们的赠款资助这些活动。商业化任务将包括 制定上市前商业计划，包括目标产品概况（TPP）、市场 研究，定价，市场，客户和竞争的综合分析，并计划 公共关系和项目管理。技术工作包括GMP批次的评价， 使用急性给药的药代动力学/药效学（PK/PD）模型的稳定性和开发。 我们还将通过一名毒理学顾问和一名首席执行官为该计划提供额外的支持。 医官。将制定涵盖IND至临床开发的知识产权计划。

TITLE: Development and Commercialization of a Tau Oligomer Inhibitor for AD/RD PROJECT SUMMARY - SBIR/STTR Commercialization Readiness Pilot (CRP) Program (PAR-19-333) 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. Our small molecule leads target tau self-association into oligomers for neurodegeneration and are therefore highly differentiated from the competition. Tau oligomers are the acutely toxic species of tau protein and their reduction will modify the course of AD. Our in vivo efficacy studies were blinded and independently performed by Peter Davies, Ph.D., a key opinion leader in the tau targeting field. In preventive studies in transgenic mice, the lead compound inhibited tau aggregation in transgenic mice expressing either human tau (htau), best representing tau aggregation in AD, or aggregation-prone, mutated tau (P301L) in the JNPL3 mouse model of inherited tauopathy. These results demonstrated 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. In vitro pharmacology tests (non-GLP) such as Ames, hERG, and DiscoverX Safety47™ panel showed good safety profiles, and the compound was highly stable in human liver microsomal stability studies. In vivo safety testing in rats (non-GLP) showed a maximum tolerated dose (MTD) of 1,000 mg/kg, and no adverse effects were found in a 14-day dose range finding study at 400 mg/kg. GLP safety studies that will support our package for FDA (Grant # AG062021) will be performed on the stable, free-base polymorph of the formulated compound. The cGMP manufacture and formulation of our lead for use in clinical development is also in progress (Grant # AG066384). This application is for commercialization activities and technical and consulting work necessary for an IND submission. There is no overlap in funding for these activities with our awarded grants. Commercialization tasks will include the development of a pre-launch commercial plan including a target product profile (TPP), market research, pricing, comprehensive analyses of the market, customers and competition, and plans for public relations and project management. Technical work includes evaluation of the GMP batch for stability and development of a pharmacokinetic/pharmacodynamic (PK/PD) model using acute dosing. We will also provide additional support for the program by a Consulting Toxicologist and a Chief Medical Officer. An intellectual property plan will be made spanning IND to clinical development.