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 目前还没有批准的疾病缓解药物来预防、延迟或减缓阿尔茨海默病的疾病进展 疾病（AD）和相关的痴呆症。绝大多数 AD 临床试验针对的是 β-淀粉样蛋白 超过 99% 的研究结果令人失望地无效。因此，迫切需要 使不同于现有技术的疾病改变方法组合多样化。我们公正的发现 这里描述的活动策略侧重于针对一种特定形式的失调炎症， 大脑中有害的促炎细胞因子过量产生，这是突触功能障碍的关键因素， 多种神经退行性疾病中的神经退行性变和认知能力下降。我们寻求资金 MW01-2-151SRM (=MW151) 需要进行 1 期临床安全性研究。 MW151 是一种新型中枢神经系统渗透剂， 口服生物可利用的小分子候选药物，可选择性抑制应激源诱导的促炎症 细胞因子过度产生。 MW151 在低剂量下可改善突触损伤和认知障碍 多种动物模型中，促炎细胞因子失调被认为是疾病的一个促成因素 进展。 MW151 在研究新药 (IND) 的安全药理学方面不承担责任，并且 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得到加强 专为要求严格的静脉给药途径及其 1a 期和 1b 阶段的前景乐观。我们假设 MW151 将成为未来成功的口头候选者 MCI/AD 患者的治疗。该应用程序旨在通过所需的首次人体试验取得进展 （FIH）安全性临床试验。我们的具体目标是： 目标 1：进行首次人体 (FIH) 1a 期单次剂量递增 (SAD) 研究。这项研究将确定 MW151 在健康成人中的安全性和耐受性、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，为未来的探索性研究提供基线数据 2a 期临床试验中的药效学 (PD) 终点。 目标 2：对 MW151 进行 1b 期多次剂量递增 (MAD) 研究。这项研究将确定安全性 健康成年志愿者中 MW151 的耐受性、最大耐受剂量和 PK。此外，还有一群 将包括老年健康受试者和脑脊液中探索性 PD 炎症细胞因子终点。 目标 3：尽早为 MW151 的未来 2a 期临床试验准备临床方案和研究者手册 广告。根据拟议的 1 期研究的结果，我们将设计 2a 期试验并准备 所需文件。这将使未来的 AD FIP 研究立即取得进展。 总体而言，MW151代表了作为一流的疾病缓解药物的独特发展机会 治疗性的。