Alzheimer's Disease Therapeutic

描述(申请人提供)：阿尔茨海默病(AD)是一种严重的神经系统疾病，困扰着超过450万美国人和全球超过1000万人。缺乏治疗阿尔茨海默病的方法将导致对更好、更安全的阿尔茨海默病药物的需求。今天市场上所有的药物都有严重的副作用。最近，位于马里兰州罗克维尔的布兰切特·洛克菲勒神经科学研究所的研究人员提出假设，并证明蛋白激酶C(PKC)及其激活是改善AD病理生理和认知损害的重要手段。他们已经证明，亚纳摩尔浓度的Bryostatin 1，一种有效的PKC激活剂，显著增加了AD患者成纤维细胞中非淀粉样变性可溶性淀粉样前体蛋白(SAPP)的生成。Bryostatin 1有效地减少了双转基因小鼠的脑淀粉样斑块(AD中的A240和A242)，同时改善了行为结果和过早死亡率。这些研究人员还表明，bryostatin 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。Bryostatin 1是一种复杂的环状大环内酯分子，在苔藓虫中以非常小的浓度(~5至25ppm)出现，有时被称为在南加州海岸发现的“海苔”。Bryostatin 1的疏水性也比紫杉醇更强，紫杉醇是一种强效抗癌药物，存在众所周知的配方困难。Aphios已经开发并申请了改进的方法和制造工艺的专利，以经济高效地从Bugula neritina中分离出药用级Bryostatin 1。我们的科学家和工程师还开发了在稳定、易于生物利用的油基配方中配制Bryostatin 1等疏水分子的方法，以及将进一步提高口服生物利用度的新型纳米技术Bryostatin 1配方。Aphios公司的Zindol(R)产品含有油溶姜辣素和shogaol，最近成功地完成了治疗接受化疗的癌症患者恶心和呕吐的第二/第三阶段临床试验。我们第一阶段的具体目标是：(1)开发Bryostatin 1的传统和纳米技术口服制剂；(2)测试选定制剂在加速温度和湿度条件下的稳定性，并评估体外特性和体内疗效。在进入第二阶段之前，我们设定了三个里程碑。我们的第一阶段里程碑如下：稳定的冻干和/或油基纳米颗粒bryostatin-1的尺寸范围为100至200 nm，包含1至10 5g/mLbryostatin 1，药物：聚合物比例为1：10至1：100；简短(5-15分钟)、低剂量(0.04-0.2 nm)和应用频率1-2倍/周将提供最大的PKC激活和最小的下调；野生型小鼠的学习记忆能力提高30%至50%，由于神经保护，转基因小鼠的学习记忆能力提高更多。我们的第二阶段具体目标如下：(1)具体目标1：对于选定的制剂，将进行放射性Bryostatin 1的检测，以确定其药代动力学和组织分布。还将通过PKC总活性、膜/胞液PKC活性比率和ERK 1/2 MAP Kinase的磷酸化来衡量药理效果，特别是在大脑和血浆中；以及(2)具体目标2：在中试水平上建立Bryostatin 1 API(活性药物成分)和FDP(最终或配方药物产品)的cGMP制造。建立药物总档案，设计支持IND的临床前研究和I/II期临床试验，并起草IND包：在第三阶段商业化工作中，我们将在良好实验室规范(GLP)条件下进行支持IND的临床前体内研究，包括毒理学、有效性、药理学和选定配方的Bryostatin 1药物产品的稳定性测试。这些研究将由南方研究所或Covance实验室等CRO进行。作为我们商业化努力的一部分，Aphios Corporation还将成立一家全资子公司Amron PharmPharmticals，专注于发现和开发以Bryostatin-1为先导化合物的治疗阿尔茨海默病和认知障碍的新疗法。阿米伦制药公司将筹集2000万美元的首轮股权资本，以加快治疗阿尔茨海默氏症和认知障碍的Bryostatin 1的开发。这笔资金将用于：(I)建立管理和产品开发团队；(Ii)进行第一阶段人体临床试验；(Iii)第二代产品的研究和开发；以及(Iv)在两年内制造cGMP产品。在首轮融资的12个月内，Amylon计划启动2500万美元的B轮融资，在第三年进行第二阶段临床试验。稍后，Amylon计划进行首次公开募股(IPO)，筹集1亿美元，用于进行第三阶段临床试验，并将治疗阿尔茨海默病和认知障碍的Bryostatin 1商业化。或者，在这个阶段，Amylon将与一家中端上市公司合并，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.