Supplemental Funding for Grant Named Safety and Pharmacokinetics of JOTROL for Alzheimer's Disease

JOTROL 治疗阿尔茨海默病的安全性和药代动力学补助金的补充资金

• 批准号: 10543909
• 负责人: Marshall Hayward
• 金额: $ 23.33万
• 依托单位: JUPITER NEUROSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-05 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543909
• 关键词: Alzheimer' s Disease; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Anti-Inflammatory Agents; Attenuated; Authorization documentation; Award; Biogenesis; Biological Availability; Biological Markers; COVID-19; Clinical Research; Clinical Trials; Data; Disease; Disease Outcome; Dose; Drug Kinetics; FGF2 gene; Food; Formulation; Funding; Grant; Histones; Inflammation; Interleukin-4; Interleukins; Legal patent; MMP9 gene; Metabolism; Mitochondria; Names; Neurodegenerative Disorders; Neurons; Oral; Outcome; Pharmacology; Phase; Placebos; Plasma; Population; Prevention; Property; RANTES; Reactive Oxygen Species; Regimen; Reporting; Resveratrol; SIRT1 gene; Safety; Sirtuins; Therapeutic; Therapeutic Effect; adaptive immunity; arm; clinical efficacy; cost; gastrointestinal; improved; liver metabolism; macrophage-derived chemokine; mental state; mitochondrial dysfunction; neuroinflammation; non-histone protein; phase 2 study; response; tau Proteins; transcription factor; volunteer; week trial

Project Summary Resveratrol has shown potential therapeutic utility in a number of disorders characterized by neuronal degradation, mitochondrial dysfunction, inflammation, and the presence of reactive oxygen species. Resveratrol has shown beneficial outcomes in Alzheimer’s Disease (AD). Resveratrol use is limited by poor bioavailability due to rapid and extensive first pass metabolism. At doses that correlate with positive disease outcomes, gastrointestinal intolerability is an issue. A high bioavailability orally administered resveratrol (JOTROL) has been developed, and a patent protecting the formulation and utility has been granted. The US FDA has authorized a single ascending dose pharmacokinetic (PK) study with food effect in order to establish dosing regimens in several proposed phase 2 clinical studies, including AD. A PK study of JOTROL is a necessary enabling trial to allow a Phase 2 study in AD, the premise of the current project. Resveratrol has previously been evaluated in AD clinical trials and evidence of a positive response with respect to Alzheimer’s biomarkers and CNS inflammation has been reported. Additionally, resveratrol has a number of pharmacologic activities that are identified as potential targets for AD. Resveratrol is a sirtuin activator (SIRT1 deacetylates histones and non-histone proteins such as transcription factors); stimulates mitochondrial biogenesis; has CNS and systemic anti-inflammatory properties; improves neuronal function; and scavenges reactive oxygen species. In a phase 2 AD study, resveratrol demonstrated stabilization of key biomarkers, including amyloid levels in CSF and plasma. Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP9 and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2. Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment attenuated declines in mini- mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial, but did not alter tau levels. Collectively, these data suggest that resveratrol decreases CSF MMP9, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a viable target for treatment or prevention of neurodegenerative disorders. Study associated population PK data show the attained plasma level in this study was too low to generate a maximal therapeutic effect of resveratrol treatment. The poor bioavailability of resveratrol due to extensive and rapid first pass liver metabolism limits utility. In all cases where biomarkers and/or clinical efficacy is observed in response to resveratrol, it is only at very high doses associated with GI intolerability. The levels of circulating resveratrol are in the range that is expected to be required to elicit the full beneficial effects of resveratrol, i.e., approximately 500 ng/ml in plasma. We have FDA authorization to conduct a PK study in normal volunteers. The proposed PK study is a single ascending dose trial with a food effect arm. The PK profile of JOTROL will inform dosing in a planned Phase 2 study in AD.

项目摘要 白藜芦醇在一些以神经元为特征的疾病中显示出潜在的治疗效果。 降解、线粒体功能障碍、炎症和活性氧物种的存在。白藜芦醇 已经显示出治疗阿尔茨海默病(AD)的有益结果。白藜芦醇的使用受到生物利用度低的限制。 由于快速而广泛的首过代谢。与阳性疾病结果相关的剂量， 胃肠道耐受性是一个问题。口服白藜芦醇(JOTROL)具有高生物利用度 已开发，并已授予保护该配方和实用新型的专利。美国FDA已授权一项 考虑食物效应的单次递增剂量药代动力学研究 几项拟议的2期临床研究，包括阿尔茨海默病。JOTROL的PK研究是实现以下目标的必要试验 允许在AD中进行第二阶段研究，这是当前项目的前提。 白藜芦醇此前曾在AD临床试验中进行过评估，并有证据表明在以下方面有积极的反应 阿尔茨海默病的生物标记物和中枢神经系统炎症已有报道。此外，白藜芦醇还具有许多 被确定为AD潜在靶点的药理活性。白藜芦醇是sirtuin激活剂(SIRT1 去乙酰化组蛋白和非组蛋白蛋白，如转录因子)；刺激线粒体 生物发生；具有中枢神经系统和全身抗炎特性；改善神经功能；清除 活性氧物种。在AD的2期研究中，白藜芦醇显示了关键生物标志物的稳定性， 包括脑脊液和血浆中的淀粉样蛋白水平。与安慰剂治疗组相比，52周时，白藜芦醇 显著降低脑脊液MMP9，升高巨噬细胞衍生趋化因子(MDC)、白细胞介素4(IL-4)和 成纤维细胞生长因子-2。与基线相比，白藜芦醇使血浆MMP10升高，而降低 IL-12P40、IL12P70和RANTES。在这个子集分析中，白藜芦醇治疗缓解了迷你 精神状态检查(MMSE)分数、日常生活能力(ADCS-ADL)分数变化和脑脊液Aβ42水平 为期52周的试验，但没有改变tau水平。总而言之，这些数据表明白藜芦醇降低了脑脊液 MMP9，调节神经炎症，并诱导获得性免疫。SIRT1激活可能是一个可行的目标 用于治疗或预防神经退行性疾病。研究相关人口PK数据显示 在本研究中达到的血药浓度太低，不能产生白藜芦醇治疗的最大疗效。 白藜芦醇的生物利用度很低，这是由于白藜芦醇在肝脏中广泛而快速的代谢，限制了它的应用。总而言之， 在观察到白藜芦醇的生物标志物和/或临床疗效的病例中，白藜芦醇仅处于非常高的水平。 与胃肠道耐受性有关的剂量。循环中的白藜芦醇水平在预期范围内 需要获得白藜芦醇的全部益处，即大约500 ng/ml的血浆浓度。我们有 FDA授权在正常志愿者中进行PK研究。拟议的PK研究是单次上升的 用食物效应臂进行剂量试验。JOTROL的PK配置文件将在AD计划的第二阶段研究中提供给药信息。