Heptax for Alcoholic Liver Disease

Heptax 治疗酒精性肝病

基本信息

批准号：
7804857
负责人：
Timothy J. King
金额：
$ 31.44万
依托单位：
CARDAX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7804857
关键词：
Adverse effects Affect Alcohol consumption Alcoholic Hepatitis Alcoholic Liver Diseases Alcohols Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Benign Bioavailable Cause of Death Cell Death Cellular Membrane Cessation of life Chronic Cicatrix Cirrhosis Clinical Trials Collaborations Contracts Cyclic GMP Deposition Detection Development Diet Disease Dose Drug Formulations Ethanol Evaluation Exhibits Fatty acid glycerol esters Fibrosis Goals Government Grant Hand Health Expenditures Heavy Drinking Hepatocyte Housing Human Human Resources Hypoxia Inflammation Inflammatory Infusion procedures Injury Investigational Drugs Investigational New Drug Application Kilogram Laboratories Left Liver Liver Failure Liver Mitochondria Liver diseases Measurement Medical Methods Minority Groups Modeling National Institute on Alcohol Abuse and Alcoholism Oral Oxidative Stress Oxygen Pathology Persons Pharmacologic Substance Phase Plants Plasma Process Production Qualifying Reporting Research Research Personnel Rodent Role Route Safety Severity of illness Signaling Molecule Small Business Innovation Research Grant Steatohepatitis Tissues Toxic effect Underserved Population Validation Vital Statistics Work analytical method animal efficacy attenuation cGMP production cost cytokine design dietary supplements experience exposed human population lipid metabolism liver transplantation method development mouse model novel pre-clinical problem drinker process optimization public health relevance small molecule web site

项目摘要

DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) is caused by excessive long term consumption of alcohol via increased oxidative stress, reduction of oxygen to liver tissue (hypoxia), altered fat metabolism, increased pro-inflammatory signaling molecules (or cytokines), and increased inflammation. ALD begins with increased fat deposit in the liver. With continued excessive alcohol consumption, disease severity increases as the inflammatory component accelerates, leading to the disease states referred to as alcoholic steatohepatitis (ASH) or alcoholic hepatitis (AH). Persistent alcohol consumption then leads to extensive liver cell death and fibrosis (scarring). Extensive fibrosis results in cirrhosis and ultimately liver failure necessitating liver transplantation. It is estimated that more than 2 million people in the U.S. have ALD and in 2006, chronic liver disease with cirrhosis was the 12th leading cause of death in the U.S. with ~46% of deaths directly related to alcohol (National Vital Statistics Reports, 2007). The overall cost of health care expenditures associated with alcohol consumption was estimated at $26 billion in 1998 in the U.S. (NIAAA website). Cardax Pharmaceuticals, Inc. (Cardax) is developing a novel, proprietary, orally bioavailable small molecule, Heptax, which exhibits robust anti-inflammatory, anti-oxidant activity in relevant animal models of ALD. The compound accumulates in cellular membranes including those of liver mitochondria where much of the pro-inflammatory oxidative stress occurs. Animal studies with oral Heptax as well as human exposure through diet or dietary supplements of the active metabolite have demonstrated an unusually benign safety profile. The goal of this Fast Track Phase I/II SBIR grant is to advance the preclinical development and understanding of Heptax for the treatment of Alcoholic Liver Disease (ALD). Specifically, the grant proposes: 1) 7 day and 4 week toxicity studies of Heptax; 2) expanding the understanding of Heptax in various animal models of liver disease; and 3) pilot plant production (including process development) of the kilogram quantities of Heptax necessary for these studies. The 4 week toxicity study reports would be suitable for inclusion as part of an Investigational New Drug (IND) application to the FDA to begin human clinical trials. Company personnel are highly qualified to supervise and coordinate this activity. Cardax also has significant in-house bioanalytical capability and will transfer its proprietary bioanalytical methods to the independent contract laboratories that will perform the bioanalysis required by the FDA. Cardax will provide oversight and validation. The additional animal efficacy work will be undertaken in collaboration with experienced investigators with Cardax personnel supplying oversight, co-design, and review capabilities. PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease affects more than 2,000,000 people in the U.S., resulting in significant illness and death with minority groups disproportionately affected. Current treatments are expensive, can have significant side effects, and are only marginally effective. A safer, more efficacious, and economical therapy for this disease would represent a major medical breakthrough for this under-served population.

描述（由申请人提供）：酒精性肝病 (ALD) 是由于长期过量饮酒导致氧化应激增加、肝组织供氧减少（缺氧）、脂肪代谢改变、促炎信号分子（或细胞因子）增加而引起的。），并增加炎症。 ALD 始于肝脏脂肪沉积增加。随着持续过量饮酒，疾病严重程度会随着炎症成分的加速而增加，导致称为酒精性脂肪性肝炎（ASH）或酒精性肝炎（AH）的疾病状态。持续饮酒会导致广泛的肝细胞死亡和纤维化（疤痕）。广泛的纤维化导致肝硬化，最终导致肝衰竭，需要肝移植。据估计，美国有超过 200 万人患有 ALD，2006 年，慢性肝病伴肝硬化是美国第 12 大死因，约 46% 的死亡与酒精直接相关（国家生命统计报告，2007 年））。 1998 年，美国与饮酒相关的医疗保健支出总成本估计为 260 亿美元（NIAAA 网站）。 Cardax Pharmaceuticals, Inc. (Cardax) 正在开发一种新型、专有的、口服生物可利用的小分子 Heptax，它在 ALD 相关动物模型中表现出强大的抗炎、抗氧化活性。该化合物积聚在细胞膜中，包括肝线粒体的细胞膜，其中大部分促炎性氧化应激发生在细胞膜中。口服 Heptax 的动物研究以及人类通过饮食或膳食补充剂接触活性代谢物的研究已经证明了其异常良好的安全性。这项快速通道 I/II 期 SBIR 资助的目标是促进 Heptax 用于治疗酒精性肝病 (ALD) 的临床前开发和理解。具体而言，该资助建议：1）对 Heptax 进行 7 天和 4 周的毒性研究； 2）扩大对Heptax在各种肝病动物模型中的认识； 3) 这些研究所需的公斤级 Heptax 的中试工厂生产（包括工艺开发）。为期 4 周的毒性研究报告适合作为向 FDA 提交的研究性新药 (IND) 申请的一部分，以开始人体临床试验。公司人员具有高素质的能力来监督和协调这项活动。 Cardax 还拥有强大的内部生物分析能力，并将将其专有的生物分析方法转移给独立合同实验室，由该实验室执行 FDA 要求的生物分析。 Cardax 将提供监督和验证。额外的动物功效工作将与经验丰富的研究人员合作进行，Cardax 人员将提供监督、共同设计和审查能力。公共卫生相关性：酒精性肝病影响着美国超过 2,000,000 人，导致严重疾病和死亡，其中少数群体受到的影响尤为严重。目前的治疗方法价格昂贵，可能有显着的副作用，而且效果有限。针对这种疾病的更安全、更有效和更经济的治疗方法对于这一服务不足的人群来说将是一项重大的医学突破。