CB1 Neutral Antagonists for Alcohol Use Disorder

摘要 响应RFA-AA-20-007，该文件呼吁开发治疗酒精使用障碍的药物 (AUD)，这项U 01申请提出研究将CB 1中性拮抗剂AM 6527推向IND- 使研究能够治疗AUD。目前AUD的治疗方法要么是行为疗法，要么仅限于药物治疗 例如双硫仑、阿坎酸和纳洛酮，它们仅限于特定的患者群体， 他们的治疗效果。鉴于这些流行病学和与澳元相关的经济问题， 迫切需要新的药理学干预，更可接受的和选择性的治疗 澳元。利莫那班是一种CB 1拮抗剂，已被证明具有不可接受的不良反应，可能导致 从它的CB 1反向激动剂作用。相比之下，AM 6527是一种新型的、选择性的CB 1大麻素受体， 缺乏反向激动剂活性的中性拮抗剂。AM 6527在啮齿类动物中的临床前药理学 在非人类灵长类动物中的这类化合物的其他原型强烈支持它们的潜力 作为AUD治疗的效用。AM 6527具有良好的安全性特征，没有不良副作用的证据 (e.g.,恶心、抑郁），已报告与CB 1受体反向激动剂，如利莫那班 和taranabant的临床前和临床研究。基于这些积极的临床前数据， 作为CB 1拮抗剂的有效性，我们计划将AM 6527推向IND研究，为 治疗AUD的首次人体研究。具体而言，我们在本U 01提案中的工作旨在满足以下要求 目的：原料药的化学、生产和控制，非GLP临床前安全性研究，包括 两个种属的hERG、遗传毒性、ADME和剂量递增研究。随后的步骤将包括： 制剂的化学、生产和控制，包括处方开发、cGMP规模放大， 稳定性和分析方法;单次和重复28天给药安全性药理学的毒代动力学， 并对产品开发规划、IND准备和临床前监管策略进行了阐述。

ABSTRACT In response to RFA-AA-20-007, which calls for the development of medications to treat Alcohol Use Disorders (AUD), this U01 application proposes research to advance the CB1 neutral antagonist AM6527 towards IND- enabling studies for treating AUD. The current therapies for AUD are either behavioral or is limited to drugs such as disulfiram, acamprosate and naltrexone, which are restricted to specific patient populations in terms of their therapeutic effects. Given these epidemiological, and economic issues related with AUD, there is an urgent need for novel pharmacological interventions that are more acceptable and selective towards treating AUD. Rimonabant, a CB1 antagonist, has proven to have unacceptable adverse effects, possibly resulting from its CB1 inverse agonist actions. In contrast, AM6527 is a novel, selective, CB1 cannabinoid-receptor neutral antagonist that is devoid of inverse agonist activity. The preclinical pharmacology of AM6527 in rodents and other prototypes within this class of compounds in nonhuman primates strongly supports their potential utility as therapy for AUD. AM6527 has a favorable safety profile, without evidence of adverse side effects (e.g., nausea, depression) that have been reported with CB1-receptor inverse agonists such as rimonabant and taranabant in preclinical and clinical studies. Based upon these positive preclinical data indicating its effectiveness as a CB1 antagonist, we plan to move AM6527 toward IND-enabling studies in preparation for first-in-man studies to treat AUD. Specifically, our work in this U01 proposal is designed to meet the following aims: Chemistry, manufacturing, and controls of drug substance, non-GLP preclinical safety studies including hERG, genotoxicity, ADME and dose escalation studies in two species. The subsequent steps will comprise: Chemistry, manufacturing, and controls of drug product including formulation development, cGMP scale-up, stability, and analytical methods; toxicokinetics with single and repeat 28-day dosing safety pharmacology, followed by advisement on product development planning, IND preparation and preclinical regulatory strategy.