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: 10382888
• 负责人: Boris Tabakoff
• 金额: $ 171.05万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382888
• 关键词: ADME Study; Adult; Age; Alcohol consumption; Alcohols; Award; Benzodiazepines; Biological Availability; Brain; Cardiovascular system; Cause of Death; Characteristics; Chemicals; Chemistry; Clinical Trials; Consumption; Cyclic GMP; Data; Disease; Dose; Double-Blind Method; Drug Kinetics; Drug or chemical Tissue Distribution; Drug usage; Economic Burden; Enrollment; Enteric Nervous System; Enzymes; Equilibrium; Excretory function; Formulation; Funding; GABA-A Receptor; Goals; Grant; Health; Heavy Drinking; Human; In Vitro; Individual; Injury; Institutional Review Boards; Intestines; Investigational Drugs; Investigational New Drug Application; Kilogram; Laboratory Study; Legal patent; Liver Cirrhosis; Malignant neoplasm of liver; Maximum Tolerated Dose; Metabolism; Methods; Modeling; Molecular Target; No-Observed-Adverse-Effect Level; Oral Administration; Outcome; Participant; Pathway interactions; Performance; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase Ia Trial; Phase Ib Clinical Trial; Phase Ib Trial; Placebo Control; Radiolabeled; Randomized; Rattus; Recovery; Reporting; Research; Rodent; Route; Safety; Site; Small Business Innovation Research Grant; Surveys; Testing; Therapeutic; Tissues; Toxicokinetics; Toxicology; United States; United States Food and Drug Administration; Work; World Health Organization; alcohol abuse therapy; alcohol misuse; alcohol relapse; alcohol use disorder; commercialization; efficacy study; efficacy testing; first-in-human; genotoxicity; gut-brain axis; in vivo; meetings; method development; novel; novel therapeutic intervention; novel therapeutics; positive allosteric modulator; receptor; recruit; respiratory; safety study; scale up; therapeutically effective

According to the 2019 National Survey on Drug Use and Health, 14.1 million adults ages 18 and older had Alcohol Use Disorder, and approximately 825,000 people indicated heavy alcohol use. However, only about 8% of individuals who had AUD in 2018 received treatment. In part, the lack of treatment results from the paucity of effective therapeutics available to treat AUD, and research is ongoing to develop new therapeutic approaches. Lohocla Research Corporation has been developing such a therapeutic, called Nezavist, which was shown in nonclinical models to reduce alcohol relapse in dependent individuals. The goal of Lohocla is to produce a treatment for individuals, including those with AUD, who wish to reduce their alcohol consumption. Nezavist acts as a positive allosteric modulator of GABA-A receptors, acting at a novel site on the receptor distinct from other modulators such as benzodiazepines. The other novel characteristic of Nezavist is its site of action within the intestine, where Nezavist modulates the activity of the enteric nervous system and produces its effect on alcohol consumption through a gut-brain communication pathway. By this means, Nezavist can influence brain activity without itself entering the brain. This application is for a Phase IIB renewal of SBIR U44AA024905, which will support the completion and submission of an IND application to the FDA and the performance of Phase1 safety and tolerability clinical trials of Nezavist. During the course of the current SBIR grant, Lohocla developed a method to scale up the synthesis of Nezavist, using flow chemistry to circumvent hazardous steps, and obtained kilogram quantities of cGMP Nezavist. A spray-dried dispersion formulation has been produced that enhances bioavailability. In vitro ADME studies were performed, including determining pathways of metabolism, and investigating metabolic processes in tissues from several species, which assisted in the choice of species for in vivo toxicology and pharmacokinetics. In vitro interactions with transporters and CYP450 enzymes were also completed. The spray-dried dispersion formulation was used to assess pharmacokinetics and toxicology in several species, and the results of the toxicology studies provide the data needed to determine the dosing levels for the first-in-human studies. A pre-IND meeting was accomplished with a favorable outcome. Overall, Lohocla has completed most of the IND-enabling studies needed to progress to clinical trials, including the development of methods for administering the drug to humans. The proposed Phase IIB renewal includes completion of the mass balance study recommended by the FDA to be included in the IND application, and synthesis of cGMP formulation that can be used in the clinical trials. Once the IND is approved, Phase 1a and Phase 1b clinical trials are proposed. Concurrent with the clinical trials, a long-term nonclinical toxicology study in rat will be performed that will be needed to provide a NOAEL in order to proceed to human laboratory studies and Phase 2 clinical trials. A commercialization plan provides information on the market potential for Nezavist. The successful completion of the Phase IIB work will provide the basis for efficacy studies of a novel therapeutic approach to reduce excessive and harmful alcohol consumption.

根据2019年全国药物使用和健康调查，1410万18岁及以上的成年人 酒精使用障碍，大约825，000人表示重度饮酒。然而，只有约 2018年，8%的AUD患者接受了治疗。在某种程度上，缺乏治疗的原因是 缺乏治疗AUD的有效疗法，正在研究开发新的治疗方法 接近。Lohocla研究公司一直在开发这样一种治疗药物，称为Nezavist， 在非临床模型中显示，可以减少依赖者的酒精复发。Lohocla的目标是 为希望减少酒精消费的个人（包括AUD患者）提供治疗。 Nezavist作为GABA-A受体的正变构调节剂，作用于受体上的新位点 与其它调节剂如苯并二氮杂卓不同。内扎维主义的另一个小说特点是它的网站， 在肠道内的作用，其中Nezavist调节肠神经系统的活动，并产生 它通过肠道-大脑交流途径对酒精消费的影响。通过这种方式，Nezavist可以 在不进入大脑的情况下影响大脑活动此申请为SBIR第IIB期续期 U44 AA 024905，将支持完成并向FDA提交IND申请， Nezavist的I期安全性和耐受性临床试验的性能。在本次SBIR期间， 格兰特，Lohocla开发了一种方法来扩大Nezavist的合成，使用流动化学来规避 危险步骤，并获得千克量的cGMP Nezavist。一种喷雾干燥的分散体制剂， 提高了生物利用度。进行体外ADME研究，包括测定 代谢途径，并研究几个物种的组织中的代谢过程， 协助选择用于体内毒理学和药代动力学的种属。体外相互作用 转运蛋白和CYP 450酶也完成了。喷雾干燥的分散体制剂用于 评估几个物种的药代动力学和毒理学，毒理学研究的结果提供了 确定首次人体研究的剂量水平所需的数据。IND前会议 以一个有利的结果完成。总的来说，Lohocla已经完成了大部分的IND研究， 需要进行临床试验，包括开发给药方法， 人类拟议的IIB期更新包括完成 FDA将其纳入IND申请，并合成可用于临床的cGMP制剂。 临床试验一旦IND获得批准，将进行1a期和1b期临床试验。的同时 在临床试验中，将在大鼠中进行长期非临床毒理学研究， a NOAEL，以便进行人体实验室研究和II期临床试验。商业化计划 提供有关Nezavist市场潜力的信息。IIB期工程的顺利完成， 为减少过量和有害酒精的新治疗方法的有效性研究提供基础 消费