Evaluation of a dual PPAR agonist for treatment of Alzheimer's disease

总结 阿尔茨海默病（AD）和相关痴呆症是影响数百万人的毁灭性疾病，但没有 存在有效的治疗选择。目前正在进行研究，作为资助的第二阶段STTR的一部分 在另外两种动物模型中测试潜在AD治疗剂OL-003的功效，并评估 药理学和毒理学。第二阶段项目的总体目标是生成所需的数据， 向FDA提交研究性新药（IND）包以获得临床试验批准。由于预算 由于局限性，无法提出IND批准所需的关键研究。因此，这一行政 补充资料旨在生成母项目范围内的其他药代动力学（PK）数据， 将有助于更完整的IND包装。 在这份行政补充文件中，提出了两个目标。在目的1中，两种不同制剂的PK分析 将在小鼠中进行OL-003的筛选，以确定IND启用研究中使用的最佳制剂， 1期临床试验。该制剂由FDA批准的佐剂/赋形剂组成，已显示 为了增强脑作用药物的PK特征，将进行头对头比较，以确定 OL-003的溶解度和脑分布。在目标2中，将评估OL-003 PK线性和组织分布 随着剂量的增加。将通过小鼠每日重复给药测定脑中OL-003的稳态 使用从目标1中选择的配方。这些数据将支持最佳OL-003给药策略， 维持安全和治疗性的脑暴露以治疗AD。本次行政审批结果 补充将加强IND申请并缩短OL-003首次人体试验的时间。

SUMMARY Alzheimer’s disease (AD) and related dementias are devastating conditions that affect millions of people, but no effective treatment options exist. Studies are currently being performed as part of the funded Phase II STTR parent award to test efficacy of a potential AD therapeutic, OL-003, in two additional animal models and assess pharmacology and toxicology. The overarching goal of the Phase II project is to generate data that is required to submit an Investigational New Drug (IND) package to the FDA for clinical trials approval. Due to budget limitations, critical studies needed for IND approval were not able to be proposed. Therefore, this administrative supplement seeks to generate additional pharmacokinetic (PK) data within the scope of the parent project that will contribute to a more complete IND package. In this administrative supplement, two aims are proposed. In aim 1, PK analysis of two different formulations of OL-003 will be performed in mice to identify the optimal formulation to be used in IND-enabling studies and Phase 1 clinical trials. The formulations, consisting of FDA approved adjuvants/excipients that have been shown to enhance the PK profile of brain-acting drugs, will be compared head-to-head to identify improvements in solubility and brain distribution of OL-003. In aim 2, OL-003 PK linearity and tissue distribution will be assessed with increasing dose. Steady state of OL-003 in the brain will be determined by repeated daily dosing in mice using the selected formulation from aim 1. These data will support the optimal OL-003 dosing strategy to maintain a safe and therapeutic brain exposure for the treatment of AD. The results from this administrative supplement will strengthen the IND application and decrease the time to OL-003 first-in-human trials.