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

项目摘要/摘要 R01 AG061898的此管理补充申请请求执行下列活动的成本 在R01项目的范围内，但在授予赠款时没有预见到。R01项目是 进行口服新型脑渗透剂MW01-2-151SRM(=MW151)的1期临床研究 可用于治疗阿尔茨海默病(AD)的生物可用小分子候选药物。MW151针对的是特定的 在大脑中形成失调的炎症，损伤性促炎细胞因子的过度产生，这是一个关键 不同类型神经退行性变中突触功能障碍、神经退行性变和认知功能下降的因素 疾病。因此，该项目正在推进一种有希望的候选药物的临床开发，该候选药物可能会 疾病修饰作用不仅在AD中，而且在其他一些中枢神经系统疾病中也有，如促炎 细胞因子失调是病理生理进展机制的一部分。因为迫切需要 开发AD的疾病修改治疗策略，关键是完成第一阶段安全性试验和 继续推动MW151向前发展。请求提供本行政副刊是因为两个原因 重大不可预见的情况。首先，1a期临床试验的进行大大延迟。 因为新冠肺炎于2020年3月对杜克大学临床站点的人体研究施加了限制。这 延迟导致有必要延长药物储存时间和进行更长期的稳定性测试 不是计划好的。其次，FDA最近在2020年9月发布了一份新的指导文件，涉及 我们需要在MW151发展计划中解决的药物中亚硝胺杂质的控制。 因此，我们将在副刊中追求两个具体目标。 目的1：对MW151原料药和制剂进行管理。我们将维持MW151药物 物质和参考标准存储，执行额外的重新测试，并对 药物物质和药物产品的持续时间比原计划的时间要长。血浆样本中的 在分析之前，MW151 PK测量值的存储时间也会比预期的更长，因此我们需要 在经过验证的生物分析方法中增加两个额外的稳定时间点。 目的2：亚硝胺评价。因为越来越多的被批准的药物已经 由于亚硝胺污染被FDA召回或临床搁置，FDA最近发布了一份 立即实施的指导性文件。因此，MW151原料药将受到亚硝胺的影响 风险评估。根据确定的风险水平，亚硝胺的存在或不存在(S)将是 用经过验证的高分辨率、高灵敏度的LC-MS方法进行测量。如果亚硝胺 污染物的存在水平高于FDA推荐的可接受摄入量限制，然后进行未来的研究 将制定战略，改变制造工艺，以减少或防止亚硝胺杂质 在MW151进入第二阶段临床试验之前。

PROJECT SUMMARY/ ABSTRACT This administrative supplement application to R01 AG061898 requests costs to perform activities that are within the scope of the R01 project, but were unforeseen at the time of award of the grant. The R01 project is to conduct phase 1 clinical studies of MW01-2-151SRM (=MW151), a novel, brain-penetrant, orally bioavailable, small molecule therapeutic candidate for Alzheimer’s disease (AD). MW151 targets 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. Thus, this project is advancing 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. Because of the urgent need to develop disease-modifying therapeutic strategies for AD, it is critical to complete the phase 1 safety trials and continue to move MW151 forward in development. This administrative supplement is requested because of two major unforeseen circumstances. First, the conduct of the phase 1a clinical trial was substantially delayed because of COVID-19 restrictions on human studies imposed in March 2020 at the Duke clinical site. This delay has resulted in the necessity for additional drug storage time and longer-term stability testing that were not planned for. Second, the FDA has recently issued a new guidance document in September 2020 related to control of nitrosamine impurities in drugs that we need to address in the MW151 development program. Therefore, we will pursue two specific aims in the supplement. Aim 1: Management of MW151 drug substance and drug product. We will maintain MW151 drug substance and reference standard storage, perform additional re-tests, and do QC and stability tests on the drug substance and the drug product over a longer time frame than originally planned. The plasma samples for MW151 PK measurements will also be stored for longer than anticipated before analysis, so we will need to add two additional stability time points to the validated bioanalytical method. Aim 2: Nitrosamine assessment. Because of the increasing number of approved drugs that have been recalled or put on clinical hold by the FDA because of nitrosamine contamination, the FDA recently issued a guidance document for immediate implementation. Therefore, MW151 API will be subjected to a nitrosamine risk assessment. Depending on the level of risk determined, the presence or absence of nitrosamine(s) will be measured with a validated high resolution, high sensitivity LC-mass spectrometry method. If a nitrosamine contaminant is present at levels above the FDA-recommended Acceptable Intake Limits, then future studies will develop strategies for changes in the manufacturing process to reduce or prevent nitrosamine impurities before MW151 is brought into phase 2 clinical trials.