Nezavist a Novel Molecule for Treatment of Alcohol Use Disorder

根据2019年全国毒品使用与健康调查，1410万18岁及以上的成年人患有 酒精使用障碍，约825,000人表示大量饮酒。然而，只有大约 2018年AUD患者中有8%接受了治疗。在一定程度上，缺乏治疗是由于 缺乏治疗AUD的有效疗法，目前正在进行研究以开发新的治疗方法 接近了。Lohocla Research Corporation一直在开发一种名为Nezavist的治疗药物，它 在非临床模型中显示可以减少依赖个人的酒精复发。Lohocla的目标是 为个人，包括那些希望减少酒精消费的澳州人提供一种治疗方法。 奈扎维斯特作为GABA-A受体的正变构调节剂，作用于受体上的一个新位置 与苯二氮卓类等其他调节剂不同。奈萨维斯特小说的另一个特点是它的地点 肠道内的活动，在那里奈扎维斯特调节肠道神经系统的活动，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，奈扎维斯特可以 在不进入大脑的情况下影响大脑活动。此申请适用于SBIR的IIB阶段续订 U44AA024905，它将支持完成IND申请并向FDA和 奈扎维斯特的1期安全性和耐受性临床试验。在当前SBIR的过程中 Grant，Lohocla开发了一种方法来放大奈扎维斯特的合成，使用流动化学来绕过 危险步骤，并获得公斤数量的cGMP奈扎维斯特。一种喷雾干燥分散体配方，具有 提高了生物利用度。进行了体外ADME研究，包括测定 代谢途径，并研究几个物种组织中的代谢过程，这些物种 协助进行体内毒理学和药代动力学的物种选择。与其体外相互作用 转运蛋白和细胞色素P450酶也已完成。喷雾干燥分散体制剂用于 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 为第一次人体研究确定剂量水平所需的数据。IND前的一次会议是 以良好的结果完成的。总体而言，Lohocla已经完成了大部分支持IND的研究 需要进展到临床试验，包括开发给药方法以 人类。拟议的第IIB阶段更新包括完成以下建议的质量平衡研究 将包括在IND申请中的FDA，以及可用于 临床试验。一旦IND获得批准，就会提出1a期和1b期临床试验。与并发 将进行临床试验，对大鼠进行长期的非临床毒理学研究，这将需要提供 A NOAEL，以便进行人体实验室研究和第二阶段临床试验。商业化计划 提供有关Nezavist的市场潜力的信息。成功完成第二期B期工程将 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。

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.