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.

补充申请摘要 我们最初项目的最终目标是完成概念验证工作， 要求的大量药效学、药代动力学、毒代动力学、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种新的化学实体， GABA-A受体上的新结合位点，并通过与肠道微生物组、肠内 神经系统和迷走神经阻断酒精消耗量明显增加 强迫戒断一段时间后的依赖性动物（复发模型）。我们已经完成了所有非- IND的临床研究，以及我们的安全性研究，我们确定了我们在人体中的治疗剂量 应该远低于产生毒性的剂量正在编写IND申请，但 在IND提交之前，关键问题仍有待解决。这个问题的核心是我们的计划， 符合FDA行业指南“1期研究药物的cGMP”。本指南详细说明了 工艺、控制、纯度和稳定性的质量检查以及用于生产 I期试验中使用的剂型。关于生产和测试的数据和信息 I期剂型必须包括在IND申请中。我们与Catalent Pharma合作， 过去开发给药动物的材料，并聘请他们生产剂型， 人类人类配方的开发、生产和控制并不是我们最初的目标。 没有为这项任务分配申请和资金。我们现在要求追加资金， 开发和生产人类剂型，以便我们能够提交IND申请。实现 这一里程碑将使我们踏上成功完成临床试验的道路， 药物治疗对那些患有AUD的人，让他们回到非成瘾的生活方式。 家长补助金申请摘要 酒精使用障碍影响了7.9%的18岁及以上的美国人口，并使社会付出了巨大的代价。 每年直接医疗费用、事故和生产力损失达2230亿美元。 目前的药物治疗只有适度的效果，必须与心理社会学结合使用。 治疗初级保健医生没有能力提供目前必要的治疗范围， 治疗AUD和适度的治疗效果产生大量的治疗失败。我们 已经产生了一种新的分子，直接作用于一种主要的神经递质受体， 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复饮模型中证明了这一点 我们的药物可以减少或防止复发我们对安全性和 我们的化合物在动物中的代谢提供了该化合物将具有良好的治疗效果的信心。 人体临床试验中的指标。然而，在进行人体试验之前，我们需要将我们的药物 被食品和药物管理局批准用于IND。为了实现这一里程碑，我们 提出了一系列SBIR I期，IND使能研究，其中包括开发口服 该制剂对于人类使用将是有吸引力的。在这些SBIR I期研究中，我们还将建立 在新开发的制剂中口服给药后，我们的药物在血液和大脑中的水平。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FDA要求的所有 IND研究，包括体外代谢和体内代谢物鉴别的完整研究 吸收、分布、代谢和排泄研究，完整的安全性和毒理学研究 （包括毒代动力学）。这些研究将包括急性剂量递增 研究以及长达六个月的亚慢性和慢性研究，因为我们预计人类 研究可能包括长期维持患者对我们的药物。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，该研究的一个分支旨在临床测量 酒精依赖者的渴望如果这笔拨款得到资助，我们的药物进入人体试验，我们 预期引入更有效和更高利用率的药物来治疗AUD。