Nezavist a Novel Molecule for Treatment of Alcohol Use Disorder

 描述(申请人提供)：酒精使用障碍影响7.9%的18岁及以上的美国人口，每年给社会造成超过2230亿美元的直接医疗成本、事故和生产力损失。目前的药物治疗仅有一定的效果，必须与心理社会治疗结合使用。初级保健医生缺乏提供目前治疗AUD所需的治疗范围的能力，治疗的适度效果导致相当数量的治疗失败。我们已经产生了一种新的分子，直接作用于一种主要的神经递质受体，这种受体因长期过量饮酒而改变。我们还在两种不同的酒精依赖动物反复饮酒模型中证明了我们的药物可以减少或防止这种复发。我们对我们化合物在动物身上的安全性和新陈代谢的初步研究提供了信心，该化合物将在人类临床试验中具有良好的治疗指标。然而，在开始人体试验之前，我们需要我们的药物获得食品和药物管理局的IND批准。为了能够完成这一里程碑，我们正在提议进行一系列SBIR第一阶段IND使能研究，其中包括开发一种对人类具有吸引力的口服配方；使用该配方在老鼠身上重复我们化合物的复发阻止作用，并将我们关于减少使用我们化合物的酒精消耗的研究扩展到非人类灵长类动物。在这些SBIR第一阶段研究中，我们还将在新开发的配方中确定口服药物后的血液和脑水平。在SBIR第二阶段研究中，我们将在cGMP条件下生产我们的药物，并扩大生产，以满足未来的临床试验。第二阶段的SBIR研究将完全集中于完成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，体内吸收、分布、代谢和排泄的研究，两个物种(老鼠和猴子)的安全性和毒理学(包括毒物动力学)的完整研究。这些研究将包括持续时间长达六个月的急性剂量研究和亚慢性和慢性研究，因为我们预计人体研究可能包括对服用我们药物的患者的长期维持。如果获得IND称号，我们预计将在这项研究的一支手臂上启动一项第一阶段的人类安全试验，旨在研究酒精依赖受试者渴望的临床指标。如果这笔资金得到资助，我们的药物达到了人体试验，我们预计将推出一种更有效、更高利用率的药物来治疗AUD。

 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.