Nezavist a Novel Molecule for Treatment of Alcohol Use Disorder

Nezavist 是一种治疗酒精使用障碍的新型分子

基本信息

批准号：
9547971
负责人：
Boris Tabakoff
金额：
$ 150万
依托单位：
LOHOCLA RESEARCH CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9547971
关键词：
Abstinence Accidents Acute Affect Age Alcohol consumption Alcohol dependence Alcohols Animals Autopsy Binding Proteins Biological Biological Availability Blood Brain Canis familiaris Cardiovascular system Carrier Proteins Chemistry Chronic Clinical Clinical Trials Consumption Cyclic GMP Cytochrome P450 Data Development Dose Drug Kinetics Drug Modelings Eligibility Determination Enzymes Equilibrium Excretory function Female Formulation Funding Future GABA-A Receptor Grant Health Health Care Costs Heavy Drinking Hepatocyte Human In Vitro Incubated Individual Kilogram Knowledge Liver Microsomes Lung Macaca mulatta Maintenance Maximum Tolerated Dose Measures Medical Metabolic Metabolism Methods Modeling Monitor Monkeys Neurotransmitter Receptor Oral Oral Administration Organ Patients Permeability Pharmaceutical Preparations Pharmacotherapy Phase Plasma Plasma Proteins Population Positioning Attribute Primary Care Physician Procedures Production Productivity Quinolones Rattus Recombinants Recovery Relapse Reporting Residual state Safety Series Site Small Business Innovation Research Grant Societies Techniques Technology Testing Therapeutic Therapeutic Index Toxicokinetics Toxicology Treatment Failure United States Food and Drug Administration World Health Organization absorption alcohol abuse therapy alcohol relapse alcohol use disorder arm base cost craving drinking drug distribution economic cost in vivo male metabolic profile nonhuman primate novel phase 1 study phase 2 study positive allosteric modulator prevent psychosocial public health relevance response scale up uptake

项目摘要

DESCRIPTION (provided by applicant): Alcohol Use Disorder affects 7.9% of the U.S. population ages 18 and older and costs society over $223 billion per year in direct medical costs, accidents and lost productivity. Current pharmacotherapy is only modestly effective and has to be used in conjunction with psychosocial treatment. Primary care physicians are ill equipped to provide the currently necessary range of therapy for treating AUD and the modest effects of therapy generate a significant number of treatment failures. We have generated a novel molecule with action directly at one of the major neurotransmitter receptors altered by chronic excessive consumption of alcohol. We have also demonstrated in two different models of relapse drinking by alcohol dependent animals that our medication can reduce or prevent such relapse. Our preliminary studies on the safety and metabolism of our compound in animals provide confidence that the compound will have a good therapeutic index in human clinical trials. Prior to embarking on the trials in humans we, however, need for our drug to be approved for an IND by the Food and Drug Administration. To be able to accomplish this milestone we are proposing a series of SBIR Phase I, IND enabling studies, which include the development of an oral formulation which will be attractive for use with humans; the use of this formulation to repeat the relapse blocking effects of our compound in rats, and to extend our studies on reducing alcohol consumption with our compound to non- human primates. In these SBIR Phase I studies we will also establish the blood and brain levels of our drug after oral administration in the newly developed formulation. In the SBIR Phase II studies we will produce our drug under cGMP conditions and scale up production to meet future clinical trials. The Phase II SBIR studies will be fully focused on completing all of the FDA required studies for the IND, including complete studies of in vitro metabolism and metabolite identification, in vivo studies of Absorption, Distribution, Metabolism, and Excretion, complete studies on safety and toxicology (including toxicokinetics) in two species (rats and monkeys). These studies will include escalating acute dose studies and sub-chronic and chronic studies of up to six months duration because we anticipate that human studies may include long term maintenance of patients on our medication. If an IND designation is obtained we anticipate launching a Phase I human safety trial with an arm of this study aimed at a clinical measure of craving in alcohol-dependent subjects. If this grant is funded and our medication reaches human trials we anticipate introducing a more efficacious and much more highly utilized medication to treat AUD.

描述（由申请人提供）：酒精使用障碍影响着 7.9% 的 18 岁及以上的美国人口，每年给社会造成的直接医疗费用、事故和生产力损失超过 2,230 亿美元。目前的药物治疗效果有限，必须使用。与心理社会治疗相结合，初级保健医生没有能力提供目前治疗 AUD 所需的一系列治疗方法，并且治疗效果有限，导致大量治疗失败。直接作用于因长期过量饮酒而改变的主要神经递质受体之一。我们还在酒精依赖动物的两种不同的复发饮酒模型中证明，我们的药物可以减少或预防这种复发。然而，在开始人体试验之前，我们的药物在动物身上的试验表明该化合物将具有良好的治疗指数，我们的药物需要获得美国食品和药物管理局的 IND 批准。能够实现我们提议的这一里程碑一系列 SBIR I 期 IND 启用研究，其中包括开发一种对人类具有吸引力的口服制剂，使用该制剂在大鼠中重复我们的化合物的复发阻断作用，并扩展我们的研究；在这些 SBIR 第一阶段研究中，我们还将确定新开发的制剂口服后药物的血液和大脑水平。在 SBIR 第二阶段研究中，我们将生产我们的药物。 cGMP条件下的药物并扩大规模II 期 SBIR 研究将完全专注于完成 FDA 要求的所有 IND 研究，包括体外代谢和代谢物鉴定的完整研究，吸收、分布、代谢和代谢的体内研究。两个物种（大鼠和猴子）的排泄、安全性和毒理学（包括毒代动力学）的完整研究将包括逐步升级的急性剂量研究以及长达六个月的亚慢性和慢性研究，因为我们预计人体研究。如果获得 IND 指定，我们预计将启动一项 I 期人类安全试验，该研究的一部分旨在对酒精依赖受试者的渴望进行临床测量。我们的药物已进入人体试验，我们预计会推出一种更有效、利用率更高的药物来治疗 AUD。