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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.

酒精使用障碍影响美国7.9%的18岁及以上人口，每年在直接医疗费用、事故和生产力损失方面的社会成本超过2230亿美元。目前的药物治疗效果有限，必须与心理治疗结合使用。初级保健医生没有能力提供目前治疗AUD所需的治疗范围，并且治疗的适度效果产生了大量的治疗失败。我们已经产生了一种新的分子，直接作用于一种因长期过量饮酒而改变的主要神经递质受体。我们还在两种不同的酒精依赖动物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。我们对我们化合物在动物中的安全性和代谢的初步研究提供了信心，该化合物将在人体临床试验中具有良好的治疗指数。然而，在进行人体试验之前，我们需要我们的药物获得食品和药物管理局的IND批准。为了能够实现这一里程碑，我们提出了一系列SBIR I期IND使能研究，其中包括开发对人类使用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，并将我们的化合物减少酒精消耗的研究扩展到非人灵长类动物。在这些SBIR I期研究中，我们还将确定新开发制剂口服给药后药物的血液和脑水平。在SBIR II期研究中，我们将在cGMP条件下生产我们的药物，并扩大生产规模以满足未来的临床试验。II期SBIR研究将完全专注于完成IND的所有FDA要求的研究，包括体外代谢和代谢产物鉴别的完整研究，吸收、分布、代谢和排泄的体内研究，以及两个种属（大鼠和猴）的安全性和毒理学（包括毒代动力学）的完整研究。这些研究将包括急性剂量递增研究以及持续时间长达6个月的亚慢性和慢性研究，因为我们预计人体研究可能包括长期维持患者使用我们的药物。如果获得IND认定，我们预计将启动一项I期人体安全性试验，该试验的一个分支旨在对酒精依赖受试者的渴望进行临床测量。如果这笔赠款得到资助，我们的药物进入人体试验，我们预计将推出一种更有效和更高利用率的药物来治疗AUD。