26- & 39-Week Toxicity Studies of ANS-6637 in Rats and Monkeys (respectively) to Enable 6+ Months Dosing in Alcohol (and other Substance) Use Disorder Phase 3 Studies

项目摘要 卫生局局长说：“药物滥用仍然是一个国家公共卫生危机。2015年，1500万 美国成年人患有酒精使用障碍（AUD）2。然而，只有不到7%的澳元收到 治疗3.在美国，88，000人死于酒精相关原因4，澳元的经济负担已经结束 每年2 500亿美元5。以解决有助于国家公共卫生危机的澳元和更广泛的物质 使用障碍（SUD），需要更多的工具，包括新的药物治疗SUD。 Amygdala正在开发新的治疗方法ANS-6637，用于AUD和SUD。拟议的具体目标将 生成确立ANS-6637作为治疗的适当治疗持续时间所需的慢性毒性数据 对于SUD。 ANS-6637是选择性醛脱氢酶2（ALDH 2）抑制剂GS-1的口服生物可利用的前药。 548351.体外和体内研究表明，ALDH 2抑制抑制多巴胺的激增 所有上瘾的人都有释放的习惯27.药理学研究表明，ALDH 2抑制降低了 渴望和药物寻求行为在多个啮齿动物模型，包括酒精复发的恢复模型。 ANS-6637已在135名人类受试者的I期临床研究中进行了研究。ANS-6637已被评估 在为期28天和13周的大鼠和猴毒性研究中，支持长达3个月的临床给药。 包括AUD在内的物质使用障碍是慢性复发性疾病。因此，SUD的治疗和 AUD应该被开发用于扩展（即，3个月以上）。对于AUD临床 根据美国食品药品监督管理局（FDA）的指导，3期试验的持续时间为6个月29。 在6个月或更长时间的人体临床研究之前，或上市暴露>1个月，FDA和 人用药品注册技术要求国际理事会（ICH）指南要求申办者进行6个月啮齿动物试验， 9-月非啮齿动物重复剂量毒性研究30，31。本补助金申请的具体目的（慢性毒性 在啮齿动物中持续6个月，在非人灵长类动物中持续9个月的测试）将生成所需数据 评估是否可以进行剂量高达600 mg QD的6个月或更长时间的临床研究。

PROJECT SUMMARY The Surgeon General has stated “substance misuse remains a national public health crisis”1. In 2015, 15 million adults had Alcohol Use Disorder (AUD) in the United States (US)2. However, less than 7% with AUD received treatment3. In the US, 88,000 people die from alcohol related causes4 and the economic burden of AUD is over $250 billion per year5. To solve help the national public health crisis of AUD and more broadly of substance use disorder (SUD), more tools including new pharmacotherapy treatments for SUD are needed. Amygdala is developing the novel treatment, ANS-6637, for AUD and SUD. The proposed Specific Aims will generate chronic toxicity data required to establish appropriate treatment duration for ANS-6637 as a treatment for SUD. ANS-6637 is an orally bioavailable prodrug of the selective Aldehyde dehydrogenase 2 (ALDH2) inhibitor GS- 548351. In-Vitro and In-Vivo studies have demonstrated that ALDH2 inhibition suppresses the surge in dopamine release common to all addiction27. Pharmacology studies have demonstrated that ALDH2 inhibition reduces craving and drug-seeking behavior in multiple rodent models including reinstatement models of alcohol relapse. ANS-6637 has been studied in Phase 1 clinical studies in 135 human subjects. ANS-6637 had been evaluated in 28-day & 13-week rat & monkey toxicity studies which support clinical dosing of up to 3-months duration. Substance Use Disorders including AUD are chronic relapsing diseases. Therefore, treatments for SUD and AUD should be developed to be used for extended (i.e., more than 3-months) duration. For AUD clinical development, Food and Drug Administration (FDA) guidance calls for Phase 3 trials of 6-months duration29. Prior to human clinical studies of 6-months or more duration, or for marketed exposure of >1 month, FDA and the International Council for Harmonisation (ICH) Guidance require that sponsors conduct 6-months rodent and 9-month non-rodent repeat dose toxicity studies30,31. The Specific Aims of this grant application (chronic toxicity testing of 6-month duration in rodents and 9-month duration in non-human primates) will generate data required to assess if clinical studies of 6-months or longer duration with doses up to 600 mg QD can be conducted.