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：
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
项目类别：
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

项目摘要

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 年全国药物使用与健康调查，1410 万名 18 岁及以上的成年人吸毒酒精使用障碍，大约 825,000 人表示酗酒。然而，仅约 2018 年患有 AUD 的人中有 8% 接受了治疗。缺乏治疗的部分原因是缺乏可用于治疗 AUD 的有效疗法，并且正在进行研究以开发新的治疗方法接近。 Lohocla Research Corporation 一直在开发一种名为 Nezavist 的治疗方法，在非临床模型中显示可以减少依赖个体的酒精复发。 Lohocla 的目标是为希望减少饮酒的个人（包括患有澳元的人）提供治疗方法。 Nezavist 作为 GABA-A 受体的正变构调节剂，作用于受体的新位点与苯二氮卓类等其他调节剂不同。 Nezavist 的另一个新颖特征是它的网站在肠道内发挥作用，Nezavist 调节肠道神经系统的活动并产生它通过肠脑通讯途径对饮酒产生影响。通过这种方式，Nezavist 可以影响大脑活动而不进入大脑。本申请适用于 SBIR 的 IIB 期更新 U44AA024905，将支持完成并向 FDA 和 FDA 提交 IND 申请 Nezavist 的 1 期安全性和耐受性临床试验的表现。在当前 SBIR 期间 Lohocla 开发了一种扩大 Nezavist 合成规模的方法，利用流动化学来规避危险步骤，并获得了千克数量的 cGMP Nezavist。喷雾干燥的分散体制剂具有已生产出增强生物利用度的产品。进行了体外 ADME 研究，包括确定代谢途径，并研究几个物种组织中的代谢过程，协助选择体内毒理学和药代动力学的物种。体外相互作用转运蛋白和CYP450酶也已完成。喷雾干燥分散制剂用于评估多个物种的药代动力学和毒理学，毒理学研究的结果提供确定首次人体研究的剂量水平所需的数据。 IND 前会议是并取得了良好的成果。总体而言，Lohocla 已完成大部分 IND 支持研究需要进行临床试验，包括开发药物给药方法人类。拟议的 IIB 期更新包括完成由 FDA 将纳入 IND 申请，并合成可用于临床试验。一旦 IND 获得批准，将提议进行 1a 期和 1b 期临床试验。并发于临床试验中，将在大鼠中进行一项长期非临床毒理学研究，需要提供 NOAEL 以便进行人体实验室研究和 2 期临床试验。商业化计划提供有关 Nezavist 市场潜力的信息。 IIB期工作的顺利完成为减少过量和有害酒精的新治疗方法的功效研究提供基础消耗。