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

• 批准号: 10321981
• 负责人: Boris Tabakoff
• 金额: $ 12.44万
• 依托单位: LOHOCLA RESEARCH CORPORATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321981
• 关键词: Abstinence; Accidents; Achievement; Acute; Address; Affect; Age; Alcohol consumption; Alcohol dependence; Alcohols; Anesthesia and Analgesia; Animals; Applications Grants; Binding Sites; Biological Availability; Blood; Brain; Canis familiaris; Cardiovascular system; Characteristics; Chemicals; Chronic; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Consumption; Cyclic GMP; Data; Development; Dosage Forms; Dose; Drug Evaluation; Drug Kinetics; Drug usage; Enteric Nervous System; Evaluation Research; Excipients; Exclusion; Excretory function; FDA approved; Food; Formulation; Funding; Future; GABA-A Receptor; Goals; Grant; Health; Health Care Costs; Heavy Drinking; Human; Hydrolysis; In Vitro; Individual; Industry; Investigational Drugs; Life Style; Maintenance; Measures; Medical Care Costs; Metabolism; Miniature Swine; Modeling; Monitor; Monkeys; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurotransmitter Receptor; Oral; Oral Administration; Oryctolagus cuniculus; Parabens; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phase I Clinical Trials; Placebos; Population; Powder dose form; Primary Care Physician; Principal Investigator; Procedures; Process; Production; Productivity; Property; Rattus; Regulation; Relapse; Reporting; Research; Resources; Rodent; Role; Safety; Series; Shipping; Small Business Innovation Research Grant; Societies; Solid; Solubility; Suspensions; Technology; Testing; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Toxicokinetics; Toxicology; Treatment Failure; United States Food and Drug Administration; Vagus nerve structure; Work; World Health Organization; Writing; absorption; addiction; alcohol abuse therapy; alcohol use disorder; arm; base; carboxylesterase; clinical toxicology; cost; craving; crystallinity; design; dosage; economic cost; experimental study; human tissue; in vivo; meetings; melting; metabolic abnormality assessment; metabolic profile; microbiome; nonhuman primate; novel; parent grant; phase 1 study; phase 1 testing; phase 2 study; phase I trial; pre-clinical; preclinical study; prevent; psychosocial; respiratory; safety study; scale up

Abstract for Supplement Application The ultimate goal for our original project was to complete the proof-of-concept work, and the multitude of pharmacodynamic, pharmacokinetic, toxicokinetic, safety, and toxicology studies required by the FDA to apply for an IND. We are fully satisfied that we have generated a new chemical entity that acts at a novel binding site on the GABA-A receptor and acts in the gut by interacting with the microbiome, the enteric nervous system and the vagus nerve to block the significantly increased alcohol consumption in alcohol dependent animals after a period of forced abstinence (model of relapse). We have completed all non- clinical studies for an IND, and from our safety studies, we determined that our therapeutic dose in humans should be well below a dose that would produce any toxicity. The IND application is being written, but a critical issue remains to be addressed prior to IND submission. This issue centers on our plans to comply with the FDA Guidance for Industry “cGMP for Phase 1 Investigational Drugs.” This Guidance details the processes, controls, quality checks on purity and stability, and fidelity of dosage delivery for producing the dosage forms to be used in the Phase 1 trials. The data and information on the production and testing of the Phase 1 dosage forms must be included with the IND application. We have worked with Catalent Pharma in the past to develop materials for dosing animals and have engaged them to produce the dosage forms for humans. The development, production, and control of formulations for humans was not an aim of our original application and funds were not allocated for this task. We are now asking for supplemental funds in order to develop and produce the human dosage forms so that we can submit the IND application. Achievement of this milestone will start us on the path for successful completion of clinical trials and to bringing an effective medication to those suffering from AUD to return them to a non-addicted lifestyle. Abstract from the Parent Grant Application 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 must 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. 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 dogs). 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.

补充应用摘要 我们原始项目的最终目标是完成概念证明工作，而 众多的药效，药代动力学，有毒动力学，安全性和毒理学研究 FDA申请IND。我们完全满意，我们已经产生了一个新的化学实体，该实体起作用 GABA-A受体上的新型结合位点，并通过与微生物组相互作用，在肠道中作用 神经系统和迷走神经，以阻止酒精的饮酒量显着增加 一段时间强迫禁欲（退休模型）后，依赖动物。我们已经完成了所有非 - 从IND和我们的安全研究中，我们确定了人类的治疗剂量 应远低于会产生任何毒性的剂量。正在编写IND应用程序，但是 关键问题仍有待提及之前解决。这个问题涉及我们遵守的计划 在FDA行业指南中，“ CGMP的1期研究药物”。本指南详细介绍了 过程，控制，质量检查纯度和稳定性以及剂量交付的保真度以生产 在1期试验中要使用的剂型。有关生产和测试的数据和信息 IND应用程序必须包括第1阶段剂型。我们已经与Catalent Pharma合作 过去开发剂量动物的材料，并与它们订婚以生产剂型 人类。人类公式的开发，生产和控制并不是我们原始的目的 申请和资金并未分配为此任务。我们现在要求提供补充资金 开发和生产人类剂型，以便我们可以提交IND应用程序。成就 这个里程碑将使我们踏上成功完成临床试验的道路，并带来有效的 给那些患有AUD的人的药物，将他们归还给他们的生活方式。 父母赠款应用程序的摘要 饮酒障碍影响18岁及以上的美国人口的7.9％，使社会使社会超过 直接医疗费用，事故和生产力损失，每年2230亿美元。 当前的药物治疗仅适度有效，必须与社会心理结合使用 治疗。初级保健医生不等同于提供当前必要的治疗范围 治疗AUD和治疗的适度作用会产生大量的治疗失败。我们 已经在主要神经递质接收器之一上直接产生了一个新型分子 随着长期过量的酒精消费而改变。 我们还在依赖酒精的动物的两种不同的救济模式中证明了 我们的药物可以减少或阻止这种缓解。我们关于安全性和 我们在动物中化合物的代谢提供了信心，该化合物将进行良好的疗法 人类临床试验中的指数。但是，在开始人类试验之前，我们需要我们的药物成为 获得食品药品监督管理局的IND批准。为了实现这一里程碑，我们是 提出一系列SBIR I期，IND促进研究，其中包括口头的发展 形成对与人类的使用很有吸引力。在这些SBIR I期研究中，我们还将建立 在新开发的配方中口服给药后，我们药物的血液和大脑水平。在 SBIR II期研究我们将在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SBIR研究将完全专注于完成所需的所有FDA IND的研究，包括对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，有关安全性和毒理学的完整研究 （包括毒药）在两种（大鼠和狗）中。这些研究将包括不断升级的急性剂量 研究以及长达六个月持续时间的研究以及次数和长期研究，因为我们预计人类 研究可能包括长期维持我们药物中的患者。如果获得了IND设计， 我们预计将通过本研究的一臂之力启动I期人类安全试验 渴望酒精依赖性受试者。如果这笔赠款是资助的，我们的药物进行了人类试验，我们 预计会引入更高效，更高级使用的药物来治疗AUD。