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

双 PPAR 激动剂治疗阿尔茨海默病的评价

• 批准号: 10814086
• 负责人: JAMES CARDELLI
• 金额: $ 24.98万
• 依托单位: OLEOLIVE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10814086
• 关键词: Adjuvant; Administrative Supplement; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Animal Model; Award; Brain; Budgets; Clinical Trials; Communities; Data; Dose; Drug Kinetics; Drug Packaging; Drug or chemical Tissue Distribution; Evaluation; Excipients; FDA approved; Formulation; Funding; Goals; Head; Health; Investigational Drugs; Investigational New Drug Application; Mus; New Drug Approvals; Parents; Peroxisome Proliferator-Activated Receptors; Persons; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Research; Small Business Technology Transfer Research; Solubility; Therapeutic; Time; drug action; effective therapy; efficacy testing; first-in-human; improved; parent project; therapeutically effective

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.

概括 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。目前正在进行的研究是 STTR 资助的第二阶段的一部分 家长奖用于在另外两个动物模型中测试潜在 AD 治疗药物 OL-003 的疗效并进行评估 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。由于预算原因 由于局限性，无法提出 IND 批准所需的关键研究。因此，本次行政 补充寻求在父项目范围内生成额外的药代动力学（PK）数据 将有助于形成更完整的 IND 包。 在这份行政补充文件中，提出了两个目标。目标 1，两种不同制剂的 PK 分析 OL-003 将在小鼠中进行，以确定用于 IND 启用研究的最佳配方， 一期临床试验。配方由经 FDA 批准的佐剂/赋形剂组成 为了增强脑作用药物的 PK 特征，将进行头对头比较以确定改进 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。 OL-003 在大脑中的稳态将通过小鼠每日重复给药来确定 使用目标 1 中选定的配方。这些数据将支持最佳 OL-003 剂量策略 保持安全和治疗性的大脑暴露来治疗 AD。本次行政执法结果 补充品将加强 IND 申请并减少 OL-003 首次人体试验的时间。