First-in-human SAD & MAD trials for MW151, a novel Alzheimer's disease drug candidate that attenuates proinflammatory cytokine dysregulation

人类首例 SAD

• 批准号: 10061521
• 负责人: LINDA J VAN ELDIK
• 金额: $ 119.36万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10061521
• 关键词: Address; Adult; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Arts; Attenuated; Award; Bioavailable; Brain; Canis familiaris; Cardiovascular system; Central Nervous System Diseases; Characteristics; Chemicals; Clinical; Clinical Investigator; Clinical Protocols; Clinical Trials; Coenzyme A; Data; Development; Disease; Disease Progression; Dose; Drug Kinetics; Elderly; Exhibits; Formulation; Functional disorder; Funding; Future; Homeostasis; Human; Immunosuppression; Impaired cognition; Individual; Inflammation; Inflammatory; Injury; Intravenous; Investigational Drugs; Maximum Tolerated Dose; Measures; Metabolic; Modeling; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Oral; Outcome; Pamphlets; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Phase Ib Clinical Trial; Plasma; Population; Predisposition; Public Health; Rattus; Risk; Route; Safety; Synapses; Testing; Therapeutic; Toxicology; analog; base; clinical development; cohort; cytokine; design; dose information; drug candidate; effective therapy; first-in-human; genotoxicity; healthy volunteer; neuroinflammation; novel; novel therapeutic intervention; phase 1 study; physical property; pre-clinical; preclinical development; prevent; respiratory; restoration; safety study; small molecule; stressor; success; volunteer

ABSTRACT There are no approved disease-modifying drugs to prevent, delay, or slow disease progression of Alzheimer's disease (AD) and related dementias. The overwhelming majority of AD clinical trials targeted the beta-amyloid pathway with disappointingly ineffective outcomes in >99% of the studies. Therefore, there is an urgent need to diversify the portfolio of disease modifying approaches that are distinct from prior art. Our unbiased discovery strategy for the campaign described here focused on targeting a particular form of dysregulated inflammation, injurious proinflammatory cytokine overproduction in the brain, that is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. We seek funding for the required phase 1 clinical safety studies of MW01-2-151SRM (=MW151). MW151 is a novel, CNS-penetrant, orally bioavailable, small molecule candidate that selectively suppresses stressor-induced proinflammatory cytokine overproduction. MW151 ameliorates synaptic damage and cognitive impairment at low doses in diverse animal models where proinflammatory cytokine dysregulation is established as a contributor to disease progression. MW151 has no liabilities in investigational new drug (IND)-enabling safety pharmacology and toxicology tests such as respiratory and cardiovascular safety pharmacology, rat and dog 28-day repeat administration toxicology, and genotoxicity. The low risk aspect of MW151 safety is reinforced by an analog developed for the demanding intravenous route of administration and its progression through phase 1a and promising status in phase 1b. We hypothesize that MW151 will be a successful oral candidate for future treatment of individuals with MCI/AD. This application seeks to progress through the required first-in-human (FIH) safety clinical trials. Our specific aims are: Aim 1: Conduct a first-in-human (FIH) phase 1a single ascending dose (SAD) study. This study will determine safety and tolerability, maximum tolerated dose, and pharmacokinetics (PK) of MW151 in healthy adult volunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratory pharmacodynamic (PD) endpoint in phase 2a clinical trials. Aim 2: Conduct a phase 1b multiple ascending dose (MAD) study of MW151. This study will determine safety and tolerability, maximum tolerated dose, and PK of MW151 in healthy adult volunteers. In addition, a cohort of elderly healthy subjects and exploratory PD inflammatory cytokine endpoints in CSF will be included. Aim 3: Prepare clinical protocol and investigators brochure for a future phase 2a clinical trial of MW151 in early AD. Based on the outcomes of the proposed phase 1 studies, we will design a phase 2a trial and prepare the documents required. This will allow immediate progress to future FIP studies for AD. Overall, MW151 represents a unique opportunity for development as a first-in-class disease-modifying therapeutic.

抽象的 没有批准的疾病改良药物可以预防，延迟或缓慢的阿尔茨海默氏病进展 疾病（AD）和相关痴呆症。绝大多数AD临床试验针对β-淀粉样蛋白 在> 99％的研究中，途径令人失望地无效。因此，迫切需要 多样化与先前艺术不同的疾病修饰方法的组合。我们无偏见的发现 此处描述的运动策略侧重于针对特定形式的失调炎症， 有害促炎细胞因子在大脑中产生过量，这是突触功能障碍的关键因素， 神经退行性疾病的神经变性和认知能力下降。我们为 MW01-2-151SRM（= MW151）的要求1阶段1临床安全研究。 MW151是一种小说，CNS-PENETRANT， 口服生物利用的小分子候选者，可有选择地抑制压力诱导的促炎性 细胞因子过量生产。 MW151减轻低剂量的突触损伤和认知障碍 促炎细胞因子失调的多种动物模型是疾病的贡献 进展。 MW151在调查新药（IND）中没有责任 - 确保安全药理学和 毒理学测试，例如呼吸和心血管安全药理学，大鼠和狗28天重复 给药毒理学和遗传毒性。 MW151安全性的低风险方面通过模拟加强 开发是为了苛刻的静脉管理途径及其在第1A阶段的发展而开发的 1B期有希望的状态。我们假设MW151将成为未来的口头候选人 MCI/AD的个体的治疗。该应用程序旨在通过所需的第一个人类进行进展 （FIH）安全临床试验。我们的具体目的是： AIM 1：进行第一阶段（FIH）1A单升剂量（SAD）研究。这项研究将确定 健康成人中MW151的安全性和耐受性，最大耐受剂量和药代动力学（PK） 志愿者。将测量血浆细胞因子水平以提供基线数据以备将来的探索性 2A期临床试验中的药效学（PD）端点。 AIM 2：进行MW151的1B阶段多升剂量（MAD）研究。这项研究将确定安全 在健康的成人志愿者中，MW151的耐受性，最大耐受剂量和PK。另外，一群 CSF中的老年健康受试者和探索性PD炎症细胞因子终点将包括在内。 AIM 3：准备临床方案和研究人员的小册 广告。根据拟议的第一阶段研究的结果，我们将设计2A期试验并准备 需要文件。这将允许立即发展为AD的未来FIP研究。 总体而言，MW151代表了作为一类疾病改良的独特发展机会 治疗性。