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

摘要 目前还没有批准的疾病修饰药物来预防、延缓或减缓阿尔茨海默氏症的疾病进展 阿尔茨海默病(AD)和相关痴呆。绝大多数AD临床试验针对的是β-淀粉样蛋白 在99%的研究中，有令人失望的无效结果。因此，迫切需要 使有别于现有技术的疾病治疗方法组合多样化。我们不偏不倚的发现 这里描述的这项运动的战略重点是针对一种特定形式的失调炎症， 脑中有害的促炎细胞因子过度产生，这是导致突触功能障碍的关键因素， 不同神经退行性疾病中的神经退行性和认知功能衰退。我们为这个项目寻求资金 MW01-2-151SRM(=MW151)所需的第一阶段临床安全性研究。MW151是一种新型的中枢神经系统渗透剂， 口服生物利用型小分子候选药物，选择性抑制应激源诱导的促炎作用 细胞因子过量生产。低剂量MW151改善小鼠突触损伤和认知功能障碍 促炎性细胞因子失调被确定为疾病诱因的多种动物模型 进步。MW151在研究新药(IND)方面没有责任-实现安全药理学和 毒理学测试，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安全的低风险方面得到了类似的加强 为要求苛刻的静脉给药途径及其在1a和1a阶段的进展而开发 1b阶段的前景看好。我们假设MW151将是未来成功的口语候选人 MCI/AD患者的治疗。这个应用程序寻求通过所需的第一个人类 (FIH)安全性临床试验。我们的具体目标是： 目的1：进行人类首例1a期单次递增剂量(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、最大耐受量和药代动力学 志愿者。将测量血浆细胞因子水平，为未来的探索提供基线数据 2a期临床试验的药效学(PD)终点。 目的2：对MW151进行1b期多次递增剂量(MAD)研究。这项研究将确定安全性 健康成人志愿者对MW151的耐受性、最大耐受量和PK。此外，还有一批 将包括老年健康受试者和探索性帕金森病患者脑脊液中炎性细胞因子终点。 目的3：为MW151早期2a期临床试验准备临床方案和研究人员手册 广告。根据拟议第一阶段研究的结果，我们将设计一项2a阶段试验，并准备 所需文件。这将使对AD的未来FIP研究立即取得进展。 总体而言，MW151代表着作为一流疾病改良剂发展的独特机会 有治疗作用。

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.