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

摘要 阿尔茨海默病(AD)和相关的痴呆症是影响数百万人的破坏性疾病，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科技研究的一部分。 父母奖在另外两个动物模型上测试潜在的AD治疗药物OL-003的疗效并评估 药理学和毒理学。第二阶段项目的主要目标是生成所需的数据 向FDA提交研究用新药(IND)包以供临床试验批准。由于预算问题 由于存在局限性，无法提出IND批准所需的关键研究。因此，这一行政管理 补充剂寻求在父项目的范围内生成额外的药代动力学(PK)数据 将为更完整的IND套餐做出贡献。 在这份行政副刊中，提出了两个目标。在目标1中，对两种不同配方进行PK分析 将在小鼠身上进行OL-003的研究，以确定用于IND使能研究和 1期临床试验。这些制剂由FDA批准的佐剂/辅料组成，已显示 为了提高脑作用药物的PK概况，将进行面对面的比较，以确定在 OL-003的溶解度和脑内分布在目标2中，将评估OL-003 PK的线性和组织分布 随着剂量的增加。OL-003在大脑中的稳定状态将通过在小鼠身上重复每日给药来确定 使用从目标1选择的配方。这些数据将支持最优的OL-003剂量策略 对于AD的治疗，保持安全和治疗性的脑暴露。这项管理工作的结果 补充剂将加强IND的应用，并减少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.