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

摘要 阿尔茨海默病(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 可用于预防、延缓或延缓AD进展的有效疗法。主要的方法基于一组 关于可用药途径和靶点的主流核心假设已经失败。因此，有必要 与过去二十年所追求的不同，新的和可选择的道路。我们的战略是瞄准一个 特殊形式的失调性神经炎症，损伤性促炎细胞因子过度生产，是一种 不同类型神经退行性疾病中突触功能障碍、神经变性和认知功能下降的关键因素 疾病。我们寻求快速通道SBIR资金用于MW01-2-151SRM(=MW151)的首次人类(FIH)研究，a 新型，中枢神经系统渗透性，口服生物利用，小分子候选药物，选择性抑制应激源- 诱导性致炎细胞因子过度产生。MW151可改善突触损伤和认知功能 建立致炎细胞因子失调的不同动物模型的低剂量损伤 作为神经损伤或神经损伤易感性的因素。MW151在化学上和 代谢稳定，在研究新药(IND)方面没有责任-实现安全药理学和 毒理学筛查遵循ICH/FDA的指导。这包括呼吸和心血管安全。 药理学筛选，大鼠和狗28天重复给药毒理学研究，以及基因毒素分析。 此外，MW151模拟器是为要求更高的静脉注射而开发的。给药的路线基本上是 在1b期临床试验中降低了风险。总体而言，MW151是一种风险极低、前景看好的临床候选药物 开发为治疗AD或相关疾病的口服制剂。 目标1：为FIH SAD试验准备监管和其他程序。任务包括准备和 所需临床试验文件的监管批准，以及测量方法的验证 人血浆中的MW151。 目的2：对MW151进行单次递增剂量(SAD)1a期试验。SAD研究将确定安全性 MW151的耐受性和最大耐受量及其在SAD中的药代动力学(PK) 健康成年志愿者的范例。将测量血浆细胞因子水平，以提供基线数据 未来1b/2a期临床试验的探索性药效学(PD)终点。 目的3：为多次递增剂量(MAD)1b期试验准备调节程序和其他程序。我们会 设计一项MW151在健康志愿者中的多重递增剂量(MAD)临床研究，包括一组 老年健康受试者。 该项目将推动一种可能具有疾病修饰作用的有前景的候选药物的临床开发。 不仅对AD，而且对其他一些中枢神经系统疾病也有影响，在这些疾病中，促炎细胞因子 调节失调是病理生理进展机制的一部分。

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.