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

一种用于AD/RD的Tau低聚物抑制剂的开发和商业化 项目摘要-SBIR/STTR商业化准备试验(CRP)计划(PAR-19-333) 该计划的长期目标是开发一种治疗阿尔茨海默氏症的小分子药物 疾病(AD)和相关痴呆(ADRD)。有一种严重的未得到满足的疾病治疗药物的需求 广告。慢性治疗策略需要经济上可行的方法，如小分子药物。我们的 小分子将靶标tau自缔合形成神经退行性变的低聚物，因此高度 从竞争中脱颖而出。Tau寡聚体是tau蛋白的剧毒物种，其 减少会改变AD的进程。我们的体内疗效研究是盲目的，独立进行的 作者彼得·戴维斯博士，他是tau靶向领域的关键意见领袖。在转基因小鼠的预防性研究中， 在表达人tau(Htau)的转基因小鼠中，铅化合物抑制tau聚集，最好的 在AD中代表tau聚集，或在JNPL3小鼠模型中代表聚集倾向的突变tau(P301L) 遗传性紧张症。这些结果表明我们的先导化合物降低了tau和tau的自缔合。 抑制不溶性tau聚集体的形成。活性从体外和细胞检测转化为In Tau聚集的活体模型验证了我们的筛选方法，并表明靶向齐聚物的形成 可以抑制整个tau聚集途径。体外药理试验(非GLP)，如Ames，Herg， 和DiscoverX Safety47™面板显示出良好的安全性，该化合物在人体内高度稳定 肝微粒体稳定性研究。大鼠体内安全性试验(非GLP)显示最大耐受量 (MTD)为1,000 mg/kg，在14天的剂量范围研究中未发现不良反应为400 mg/kg。 GLP安全性研究将支持我们的FDA一揽子计划(GRANT#AG062021)，将在马厩上进行， 配方化合物的游离碱晶型。国产铅的cGMP生产与配方 临床开发也在进行中(赠款#AG066384)。此应用程序用于商业化 IND提交所需的活动、技术和咨询工作。没有重叠的部分 用我们的奖助金为这些活动提供资金。商业化任务将包括 制定包括目标产品简介(TPP)、市场的投放前商业计划 研究、定价、对市场、客户和竞争的全面分析，以及计划 公共关系和项目管理。技术工作包括对GMP批次的评估 急性给药的药代动力学/药效学(PK/PD)模型的稳定性和发展。 我们还将由一名咨询毒理学家和一名首席执行官为该计划提供额外的支持 医官。将制定一项从IND到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.