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

项目摘要 白藜芦醇已显示出潜在的治疗效用，在一些疾病的特点是神经元 降解、线粒体功能障碍、炎症和活性氧的存在。藜芦醇 在阿尔茨海默病（AD）中显示出有益的结果。白藜芦醇的使用受到生物利用度差的限制 由于快速和广泛的首过代谢。在与积极疾病结果相关的剂量下， 胃肠道不耐受是一个问题。高生物利用度口服白藜芦醇（JOTROL）已被 已开发，并已授予保护配方和实用性的专利。美国FDA已批准一项 考虑食物效应的单次给药剂量递增药代动力学（PK）研究，以确定 几项拟议的2期临床研究，包括AD。JOTROL的PK研究是一项必要的使能试验， 允许在AD中进行2期研究，这是当前项目的前提。 白藜芦醇先前已在AD临床试验中进行了评估，并有证据表明， 阿尔茨海默氏症的生物标志物和中枢神经系统炎症。此外，白藜芦醇具有许多 药理活性，被确定为AD的潜在靶标。白藜芦醇是一种去乙酰化酶激活剂（SIRT 1 使组蛋白和非组蛋白蛋白如转录因子脱乙酰基）;刺激线粒体 生物发生;具有CNS和全身抗炎特性;改善神经元功能;和清除 活性氧在一项II期AD研究中，白藜芦醇表现出关键生物标志物的稳定性， 包括CSF和血浆中的淀粉样蛋白水平。与安慰剂治疗组相比，在52周时，白藜芦醇 CSF MMP 9显著降低，巨噬细胞源性趋化因子（MDC）、白细胞介素（IL）-4和 成纤维细胞生长因子（FGF）-2。与基线相比，白藜芦醇增加血浆MMP 10和降低血浆MMP 10水平。 IL-12 P40、IL-12 P70和RANTES。在这个亚组分析中，白藜芦醇治疗减弱了微 治疗期间的精神状态检查（MMSE）评分、ADL（ADCS-ADL）评分变化和CSF Aβ42水平 52周的试验，但没有改变tau水平。总的来说，这些数据表明，白藜芦醇降低CSF MMP 9调节神经炎症，并诱导适应性免疫。SIRT 1激活可能是一个可行的目标 用于治疗或预防神经变性疾病。研究相关群体PK数据显示， 本研究中获得的血浆水平太低，不能产生白藜芦醇治疗的最大治疗效果。 白藜芦醇的生物利用度差，由于广泛和快速的首过肝脏代谢限制了效用。在所有 在响应于白藜芦醇观察到生物标志物和/或临床功效的情况下，其仅在非常高的浓度下存在。 与GI不耐受相关的剂量。循环中白藜芦醇的水平在预期的范围内， 需要引起白藜芦醇的全部有益效果，即，血浆中约500 ng/ml。我们有 FDA授权在正常志愿者中进行PK研究。拟定的PK研究是一项单次递增 JOTROL的PK特征将为计划的AD II期研究中的剂量提供信息。

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.