First-in-human study of MW151, a novel drug targeting neuroinflammation

MW151（一种针对神经炎症的新型药物）的首次人体研究

• 批准号: 9922418
• 负责人: Victor Shifrin
• 金额: $ 115.79万
• 依托单位: IMMUNOCHEM THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922418
• 关键词: Address; Adult; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animal Model; Anti-inflammatory; Attenuated; Automobile Driving; Bioavailable; Brain; Canis familiaris; Cardiovascular system; Central Nervous System Diseases; Chemicals; Clinical; Clinical Research; Clinical Trials; Clinical Trials Data Monitoring Committees; Cognition Disorders; Country; Data; Data Base Management; Disease; Disease Progression; Dose; Drug Kinetics; Elderly; Encephalitis; Exhibits; Formulation; Functional disorder; Funding; Future; Genetic; Grant; Homeostasis; Human; Immunosuppression; Impaired cognition; Individual; Inflammation; Intellectual Property; Investigational Drugs; Label; Legal patent; Maximum Tolerated Dose; Measurement; Measures; Metabolic; Methods; Monitor; Nerve Degeneration; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Oral; Outcome; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology and Toxicology; Phase; Plasma; Predisposition; Preparation; Process; Production; Protocols documentation; Public Health; Rattus; Reference Standards; Risk; Route; Safety; Small Business Innovation Research Grant; Synapses; Therapeutic; Time; Tissues; Toxic effect; Toxicology; United States; Validation; analog; attenuation; base; clinical candidate; clinical development; cohort; cytokine; design; drug candidate; effective therapy; first-in-human; healthy volunteer; human study; neuroinflammation; new therapeutic target; novel; novel therapeutics; off-patent; pharmacovigilance; preclinical development; preclinical safety; prevent; repaired; respiratory; response; safety study; small molecule; small molecule therapeutics; stressor; volunteer

ABSTRACT Alzheimer's disease (AD) is one of the largest global public health crises facing us today, yet there are no effective therapies available to prevent, delay, or slow AD progression. Dominant approaches based on a set of prevailing core hypotheses about druggable pathways and targets have failed. Therefore, there is a need for novel and alternative pathways distinct from those pursued over the past two decades. Our strategy is to target a particular form of dysregulated neuroinflammation, injurious proinflammatory cytokine overproduction that is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. We seek Fast-Track SBIR funding for a first-in-human (FIH) study of MW01-2-151SRM (=MW151), a novel, CNS-penetrant, orally bioavailable, small molecule drug 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 neurologic injury or susceptibility to neurologic injury. MW151 is chemically and metabolically stabile, has no liabilities in investigational new drug (IND)-enabling safety pharmacology and toxicology screens following ICH/FDA guidance. These include respiratory and cardiovascular safety pharmacology screens, rat and dog 28-day repeat administration toxicology studies, and genotox analyses. Further, a MW151 analog developed for the more demanding i.v. route of administration has been substantially de-risked in a phase 1b clinical trial. Overall, MW151 is a highly de-risked and promising candidate for clinical development as an oral formulation for the treatment of AD or related disorders. Aim 1: Prepare regulatory and other processes for a FIH SAD trial. The tasks include preparation and regulatory approval of required clinical trial documents, and the validation of methods for measurement of MW151 in human plasma. Aim 2: Conduct a single ascending dose (SAD) phase 1a trial of MW151. The SAD study will determine safety and tolerability and maximum tolerated dose of MW151 as well as its pharmacokinetic (PK) profile in a SAD paradigm in healthy adult volunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratory pharmacodynamic (PD) endpoint in phase 1b/2a clinical trials. Aim 3: Prepare regulatory and other processes for a multiple ascending dose (MAD) phase 1b trial. We will design a multiple ascending dose (MAD) clinical study of MW151 in healthy volunteers, including a cohort of elderly healthy subjects. This project will advance clinical development of a promising drug candidate that could have disease-modifying effects not only in AD but also in a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the pathophysiology progression mechanism.

抽象的 阿尔茨海默氏病（AD）是当今我们面临的最大的全球公共卫生危机之一，但没有 有效的疗法可预防，延迟或减缓AD的进展。基于一组 关于可毒途径和目标的核心核心假设失败了。因此，需要 新颖和替代途径与过去二十年来所追求的途径不同。我们的策略是针对 神经炎症失调的特殊形式，有害促炎细胞因子过量产生的特殊形式 突触功能障碍，神经退行性变化和认知能力下降的关键因素不同 疾病。我们为MW01-2-151SRM（= MW151）的首次人类（FIH）寻求快速轨道SBIR资金 新颖的，CNS-PENETRANT，口服生物利用，小分子候选药物，可有选择地抑制应激源 诱导的促炎细胞因子过量生产。 MW151改善突触损伤和认知 在促炎细胞因子失调的各种动物模型中，低剂量的损伤是 作为神经系统损伤或神经系统损伤的敏感性的贡献者。 MW151是化学上的， 代谢上稳定，没有负责调查新药（IND）的责任 - 确保安全药理学和 ICH/FDA指导后的毒理学筛选。这些包括呼吸和心血管安全 药理学筛查，大鼠和狗28天重复给药毒理学研究以及Genotox分析。 此外，MW151类似物为更苛刻的i.v.开发了类似物。管理途径已经大大 在1B期临床试验中脱离风险。总体而言，MW151是临床的高风险和有前途的候选人 开发作为治疗AD或相关疾病的口服表述。 目标1：为SAD审判准备监管和其他过程。任务包括准备和 监管部门批准所需的临床试验文件，以及测量方法的验证 MW151在人血浆中。 AIM 2：进行MW151的单一升剂剂量（SAD）1A期试验。悲伤的研究将确定安全性 在SAD中 健康的成人志愿者的范式。将测量血浆细胞因子水平以提供A的基线数据 1b/2a临床试验中的未来探索性药效学（PD）端点。 AIM 3：准备多个上升剂量（MAD）1B试验的调节和其他过程。我们将 设计健康志愿者的MW151的多重升剂临床研究，包括一群 老年人健康的受试者。 该项目将推动有前途的候选药物的临床开发 不仅在AD中，而且在促炎细胞因子的其他许多其他中枢神经系统疾病中的影响 失调是病理生理进展机制的一部分。