Alzheimer's Disease Therapeutic

阿尔茨海默病治疗

• 批准号: 7917968
• 负责人: TREVOR P. CASTOR
• 金额: $ 46.37万
• 依托单位: APHIOS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7917968
• 关键词: Adverse effects; Affect; Agitation; Alzheimer' s Disease; American; Americas; Amyloid beta-Protein; Animal Model; Antineoplastic Agents; Behavioral; Bioavailable; Biological Assay; Biological Availability; Bladder Control; Brain; California; Cancer Patient; Capital; Cause of Death; Cells; Cerebral cortex; Cessation of life; Characteristics; Clinical Trials; Cognition Disorders; Cognitive; Complex; Cyclic GMP; Defecation; Demographic Aging; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Drug Formulations; Drug Kinetics; Drug or chemical Tissue Distribution; Emotional; Engineering; Europe; Face; Fibroblasts; Frequencies; Functional disorder; Generations; Hippocampus (Brain); Human; Humidity; Impaired cognition; In Vitro; Institutes; Japan; Judgment; Laboratories; Language; Lead; Learning; Legal patent; Macrolides; Marketing; Measures; Medical; Memory; Methodology; Methods; Mitogen Activated Protein Kinase 1; Mosses; Nanotechnology; Nausea; Neurons; Neurosciences; Oils; Oral; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phosphorylation; Plasma; Polymers; Population; Preventive; Product R; Protein Kinase C; Quality of life; Radioactive; Research Institute; Research Personnel; Running; Scientist; Sea; Senile Plaques; Series; Short-Term Memory; Staging; Symptoms; Temperature; Therapeutic; Time; Toxicology; Transgenic Mice; United States; Vomiting; Wild Type Mouse; base; behavior change; brain tissue; bryostatin; chemotherapy; citrate carrier; commercialization; cost; demographics; design; dosage; good laboratory practice; improved; in vivo; manufacturing process; meetings; membrane activity; nanoparticle; nervous system disorder; neuroprotection; novel; novel therapeutics; pre-clinical; preclinical study; premature; product development; public health relevance; research and development; shogaol; stability testing

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. PUBLIC HEALTH RELEVANCE: Alzheimer's Disease (AD) is the third largest cause of death in America and among the highest in the industrial world. AD is a significant neurological disorder that affects more than 4.5 million Americans and more than 10 million people worldwide. This problem will increase with the demographics of aging populations in United States, Europe and Japan. Experts estimate that 22 million people around the world and more than 8 million Americans would be affected with AD by 2025. The total market of AD drugs in 2005 was over $2.7 billion. Due to the changing demographics, the market is expected to grow quickly. Because of the growing number of new cases each year, the market is expected to grow at a rate of 17.5%. To meet this unmet medical need and market demand, we propose to develop a novel therapeutic that has the potential to significantly reduce the personal quality of life and national financial impact of this debilitating disease.

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，困扰着超过 450 万美国人和全世界超过 1000 万人。 AD 缺乏治愈方法将导致对更好、更安全的 AD 药物的需求。当今市场上的所有药物都有严重的副作用。最近，马里兰州罗克维尔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 病理生理学和认知障碍的重要手段。他们表明，亚纳摩尔浓度的苔藓抑素 1（一种有效的 PKC 激活剂）可显着增强 AD 患者成纤维细胞中非淀粉样蛋白形成的可溶性淀粉样前体蛋白 (sAPP) 的生成。苔藓抑素 1 可有效减少双转基因小鼠的脑部淀粉样斑块（AD 中的 A240 和 A242），同时改善行为结果和过早死亡率。这些研究人员还表明，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。苔藓抑素 1 是一种复杂的环状大环内酯分子，在苔藓虫中的浓度非常低（约 5 至 25 ppm），有时被称为南加州海岸发现的“海苔”。苔藓抑素 1 也比紫杉醇更具疏水性，紫杉醇是一种有效的抗癌药物，但众所周知，其配方存在困难。 Aphios 开发了改进的方法和制造工艺，并获得了专利，用于经济有效地从 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在稳定、易于生物利用的油基制剂中配制疏水性分子（例如苔藓抑素 1）的方法，以及苔藓抑素 1 的新型纳米技术制剂，可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烯酚，最近成功完成了针对接受化疗的癌症患者的恶心和呕吐的 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 的常规和纳米技术口服制剂； (2)测试所选制剂在温度和湿度加速条件下的稳定性，并评估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。我们的第一阶段里程碑如下：稳定的冻干和/或油基苔藓抑素-1纳米颗粒制剂，尺寸范围为100至200 nm，含有1至10 5g/mL的苔藓抑素1，药物与聚合物的比例为1: 10 至 1:100；简短（5-15 分钟）、低剂量（0.04-0.2 nM）和每周 1-2 次的应用频率将提供最大程度的 PKC 激活和最小程度的下调；由于神经保护作用，野生型小鼠的学习和记忆能力提高了 30% 至 50%，转基因小鼠的学习和记忆能力增强甚至更大。我们的 II 期具体目标如下： (1) 具体目标 1：对于选定的制剂，将测定放射性苔藓抑素 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，通过总 PKC 活性、膜/胞质 PKC 活性比以及 ERK 1/2 MAP 激酶的磷酸化； (2) 具体目标 2：在中试规模建立苔藓抑素 1 API（活性药物成分）和 FDP（最终或配制的药品）的 cGMP 生产。建立药物主文件，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 III 期商业化工作中，我们将进行支持 IND 的临床前体内研究，包括毒理学、功效、药理学和在良好实验室规范 (GLP) 条件下对苔藓抑素 1 药品的选定配方进行稳定性测试。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 Corporation 还将建立一家全资子公司 Amylon Pharmaceuticals，专注于发现和开发以苔藓抑素-1 作为主要化合物的阿尔茨海默病和认知障碍的新型疗法。 Amylon Pharmaceuticals 将筹集 2000 万美元的 A 轮股权资本，以加速治疗阿尔茨海默病和认知障碍的苔藓抑素 1 的开发。这笔资金将用于： (i) 建立管理和产品开发团队； (ii) 进行第一期人体临床试验； (iii) 第二代产品的研发； (iv) 在两年内生产 cGMP 产品。 A 轮融资后 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 IPO 筹集 1 亿美元，进行 III 期临床试验苔藓抑素 1 治疗阿尔茨海默病和认知障碍的试验和商业化。或者，在这个阶段，Amylon 将与一家中型上市公司合并或被一家跨国制药公司收购。 公共健康相关性：阿尔茨海默氏病 (AD) 是美国第三大死因，也是工业世界中最严重的死因之一。 AD 是一种严重的神经系统疾病，影响着超过 450 万美国人和全世界超过 1000 万人。随着美国、欧洲和日本人口老龄化，这个问题将会加剧。专家估计，到2025年，全球将有2200万人，超过800万美国人将受到AD的影响。2005年AD药物的总市场超过27亿美元。由于人口结构的变化，预计市场将快速增长。由于每年新增病例数量不断增加，预计该市场将以 17.5% 的速度增长。为了满足这种未满足的医疗需求和市场需求，我们建议开发一种新型疗法，有可能显着降低这种使人衰弱的疾病的个人生活质量和国家财政影响。