Alzheimer's Disease Therapeutic

描述（由申请人提供）：阿尔茨海默病（AD）是一种严重的神经系统疾病，折磨着超过450万美国人和全球超过1000万人。阿尔茨海默病无法治愈将导致对更好、更安全的阿尔茨海默病药物的需求。现在市场上所有的药物都有严重的副作用。最近，马里兰州Rockville的Blanchette Rockefeller神经科学研究所的研究人员假设并证明了蛋白激酶C （PKC）及其激活是改善AD病理生理和认知障碍的重要手段。他们发现，亚纳摩尔浓度的bryostatin 1（一种有效的PKC激活剂）可显著增强AD患者成纤维细胞中非淀粉样蛋白可溶性淀粉样前体蛋白（sAPP）的生成。苔藓虫素1可有效减少双转基因小鼠的脑淀粉样斑块（AD中的A240和A242），同时改善行为结果和过早死亡率。这些研究人员还发现苔藓抑素1不仅能产生神经保护作用，还能增强AD动物模型的认知记忆。苔藓虫素1是一种复杂的环状大环内酯分子，在苔藓虫体内的浓度非常低（约5至25 ppm），有时被称为南加州海岸外的“海苔”。苔藓虫素1也比紫杉醇更疏水，紫杉醇是一种众所周知的配方困难的强效抗癌药物。Aphios已经开发并申请了改进的方法和制造工艺的专利，以经济有效地从布古拉（Bugula neritina）中分离药用级苔藓抑素1。我们的科学家和工程师还开发了制备疏水分子的方法，如苔藓虫素1在稳定、易于生物利用的油基配方中，以及新的纳米技术配方苔藓虫素1，这将进一步提高口服生物利用度。Aphios的Zindol(R)产品含有油溶性姜辣素和姜酚，最近成功完成了用于化疗癌症患者恶心和呕吐的II/III期临床试验。我们第一阶段的具体目标是：(1)开发苔藓抑素1的常规和纳米口服配方；(2)在加速温度和湿度条件下测试所选制剂的稳定性，并评价其体外特性和体内功效。在进入第二阶段之前，我们设定了三个要实现的里程碑。我们的I期里程碑如下：苔藓虫素-1的稳定冻干和/或油基纳米颗粒配方，尺寸范围为100至200 nm，含有1至10 5g/mL苔藓虫素1，药物：聚合物比例为1:10至1:100；短时间（5-15分钟），低剂量（0.04-0.2 nM）和应用频率1-2 x /周将提供最大的PKC激活和最小的下调；野生型小鼠的学习和记忆能力提高了30%到50%转基因小鼠的学习和记忆能力甚至更高，这是由于神经保护作用。我们的II期具体目标如下：(1)具体目标1：对于选定的配方，将检测放射性苔藓抑素1，以确定药代动力学和组织分布。还将测量药理学功效，特别是在脑和血浆区室中，通过PKC总活性、膜/细胞质PKC活性比和ERK 1/2 MAP激酶磷酸化来测量；(2)具体目标2：在中试水平建立苔藓虫素1原料药（活性药物成分）和FDP（最终或制剂）的cGMP生产。建立药物主文件，设计IND的临床前研究和I/II期临床试验，并起草IND包装：在III期商业化努力中，我们将进行IND的临床前体内研究，包括在良好实验室规范（GLP）条件下选定的bryostatin 1药物制剂的毒理学、疗效、药理学和稳定性测试。这些研究将由南方研究所或科文斯实验室等CRO进行。作为我们商业化努力的一部分，Aphios公司还将建立一个全资子公司Amylon制药公司，专注于以苔藓虫素-1为先导化合物的阿尔茨海默病和认知障碍的新疗法的发现和开发。Amylon Pharmaceuticals将筹集2000万美元的a轮股权资本，以加速用于阿尔茨海默病和认知障碍的bryostatin 1的开发。这笔资金将用于：(i)建立一个管理和产品开发团队；（ii）进行I期人体临床试验；（三）第二代产品的研发；（iv）在两年时间内生产cGMP产品。在A轮融资后的12个月内，Amylon计划启动2500万美元的B轮融资，在第三年进行II期临床试验。随后，Amylon计划进行首次公开募股，筹集1亿美元，进行III期临床试验，并将苔藓抑素1商业化，用于治疗阿尔茨海默病和认知障碍。或者，在这个阶段，Amylon将与一家中型上市公司合并，或者被一家跨国制药公司收购。

DESCRIPTION (provided by applicant): Alzheimer's Disease (AD) is a significant neurological disorder that afflicts more than 4.5 million Americans and more than 10 million people worldwide. The lack of a cure for AD will result in a demand for better and safer AD drugs. All of the drugs on the market today have serious side effects. Recently, researchers at The Blanchette Rockefeller Neurosciences Institute, Rockville, MD have hypothesized and shown that protein kinase C (PKC) and its activation are important means of ameliorating AD pathophysiology and cognitive impairment. They have shown that sub-nanomolar concentrations of bryostatin 1, a potent PKC activator, dramatically enhance the generation of non-amyloidogenic soluble amyloid precursor protein (sAPP) in fibroblasts from AD patients. Bryostatin 1 was effective in reducing brain amyloid plaques (A240 and A242 in AD) in double-transgenic mice while improving behavioral outcomes and the rate of premature death. These researchers have also shown that bryostatin 1 not only produces a neuroprotective effect but also enhances cognitive memory in AD animal models. Bryostatin 1 is a complex cyclic macrolide molecule that occurs in very small concentrations (~ 5 to 25 ppm) in a bryozoan, sometimes referred to as a "sea moss" found off the coast in Southern California. Bryostatin 1 is also more hydrophobic than paclitaxel, the potent anticancer drug with well-known formulation difficulties. Aphios has developed and patented improved methodologies and manufacturing processes for cost-effectively isolating pharmaceutical-grade bryostatin 1 from Bugula neritina. Our scientists and engineers have also developed methods for formulating hydrophobic molecules such as bryostatin 1 in stable, readily bioavailable oil-based formulations, and novel nanotechnology formulations of bryostatin 1 that will further improve oral bioavailability. Aphios' Zindol(R) product, which contains oil soluble gingerols and shogaols, recently completed a successful Phase II/III clinical trial for nausea and emesis in cancer patients undergoing chemotherapy. Our Phase I Specific Aims are to: (1) Develop conventional and nanotechnology oral formulations of bryostatin 1; and (2) Test stability of selected formulations under accelerated conditions of temperature and humidity, and evaluate in vitro characteristics and in vivo efficacy. We have set three milestones to be achieved before moving on to Phase II. Our Phase I milestones are as follows: stable lyophilized and/or oil-based nanoparticles formulation of bryostatin-1 in the size range of 100 to 200 nm range containing 1 to 10 5g/mL bryostatin 1 with a drug:polymer ratios of 1:10 to 1:100; brief (5-15 minutes), low dosages (0.04-0.2 nM) and application frequencies 1-2 x /week will provide maximal PKC activation and minimal downregulation; and 30% to 50% enhancement of learning and memory in the wild type of mice and even greater enhancement in the transgenic mice due to neuroprotection. Our Phase II Specific Aims are as follows: (1) Specific Aim 1: For selected formulations, radioactive bryostatin 1 will be assayed to determine the pharmacokinetics and tissue distribution. Pharmacologic efficacy will also be measured, particularly in the brain and plasma compartments by total PKC activity, membrane/cytosolic PKC activity ratios, and phosphorylation of ERK 1/2 MAP Kinase; and (2) Specific Aim 2: Establish cGMP manufacturing of the bryostatin 1 API (active pharmaceutical ingredient) and FDP (final or formulated drug product) at the pilot-scale level. Establish a Drug Master File, design IND-enabling preclinical studies and Phase I/II clinical trials, and draft IND package: In a Phase III commercialization effort, we will conduct IND-enabling preclinical in vivo studies, including toxicology, efficacy, pharmacology and stability testing of selected formulation of bryostatin 1 drug product under Good Laboratory Practices (GLP) conditions. These studies will be conducted by a CRO such as Southern Research Institute or Covance Laboratories. As part of our commercialization effort, Aphios Corporation will also establish a wholly owned subsidiary Amylon Pharmaceuticals to focus on the discovery and development of novel therapeutics for Alzheimer's Disease and Cognitive Disorders with bryostatin-1 as its lead compound. Amylon Pharmaceuticals will raise a Series A round of $20 million USD in equity capital to accelerate the development of bryostatin 1 for Alzheimer's Disease and Cognitive Disorders. This capital will be utilized to: (i) establish a management and product development team; (ii) conduct Phase I human clinical trials; (iii) research and development of second- generation products; and (iv) manufacture cGMP products over a two-year period. Within 12 months of the Series A raise, Amylon plans to initiate the establishment of a $25 million USD Series B round to conduct Phase II clinical trials in year 3. Later, Amylon plans to do an IPO to raise $100 million to conduct Phase III clinical trials and commercialize bryostatin 1 for Alzheimer's Disease and Cognitive Disorders. Alternatively, at this stage, Amylon will merge with a mid-tier public company or be acquired by a multinational pharmaceutical company.