DEVELOPMENT OF A NOVEL DRUG CANDIDATE WITH A FIRST-in-CLASS MECHANISM FOR SMOKING CESSATION, RELAPSE and ABSTINENCE

摘要 本申请是对PAR-18-219《药物开发的重大机遇》的响应 《物质使用障碍》，建议推进新型小分子药物的工业开发 拥有一种新的一流机制的候选人，作为戒烟、预防复发的药物治疗 以及长期禁欲。在药物治疗的初步戒烟后，再次吸烟是非常常见的 这是一项重大的临床挑战。所有三种药物疗法的24周戒断率 仍然很差，平均只有22%的瓦伦尼克林，16%的安非他酮和16%的尼古丁替代品 治疗，相比之下，安慰剂的比例为9%。在目前的药物疗法中，这些较差的禁酒率是 不足以全面减少烟草危害，因为烟草使用仍然是主要的可预防的 发达国家的死因和发病率。尽管存在明显的需求和可能产生的重大影响，但 十多年来一直没有新的药物疗法被批准用于戒烟 批准。迫切需要新的方法和新的药物疗法来减少渴望和 故态复萌，可促进持续禁欲。此应用程序旨在推动IND开发一个 具有一流的预防复发和戒烟新机制的新药物疗法， 这在减少线索诱导、应激诱导和尼古丁诱导的临床前疗效方面显示出显著的效果。 复发和尼古丁自我给药。主要候选药物是一种新的分子实体，其靶向是一种新的 药理机制，α3β4烟碱型乙酰胆碱受体(NAChR)。α3β4 nAChR清晰 在尼古丁依赖和药物复发机制中发挥作用，并在全基因组研究中 大量吸烟者发现编码α3、β4和α5亚基的基因多态性 NAChR与尼古丁依赖和无法戒烟的风险增加有关。领先的候选人 建议开发的是选自一系列新的高效和选择性的α3β4nAChR配体， 据我们所知，它们是已报道的一些最具选择性的α3β4nAChR配体。重要的是，他们的 强烈建议，在阻止尼古丁寻求恢复(一种复发模型)方面具有极好的体内疗效 靶向α3β4 nAChR可能提供了比现有治疗更好的配置文件，特别是对于 改善长期禁欲，防止复发。我们已经完成了几项临床前毒理学和 DMPK研究确认了IND-Enabling研究的主要候选人的适宜性。我们建议 继续开发并提交IND，以实现对这一首创的- 人类临床试验中的分类机制。根据到目前为止的结果，我们预计我们将能够 推动该候选药物的未来临床开发成为成功的戒烟药物 而且是安全有效的戒烟和长期禁欲的选择。

ABSTRACT This application, in response to PAR-18-219 `Grand Opportunity in Medications Development for Substance-use Disorders', proposes to advance the IND-enabling development of a novel small-molecule drug candidate with a novel first-in-class mechanism as pharmacotherapy for smoking cessation, relapse prevention and longterm abstinence. Relapse to smoking is very common after initial abstinence with pharmacotherapy and represents a major clinical challenge. 24-week abstinence rates for all three available pharmacotherapies is still poor and averages only 22% for varenicline, 16% for bupropion, and 16% for nicotine replacement therapies, compared to 9% for placebo. These poor abstinence rates with current pharmacotherapies are inadequate for overall tobacco harm reduction, given that tobacco use still remains the leading preventable cause of death and morbidity in the developed world. Despite the clear need and possible high impact, there have been no new pharmacotherapy approved for smoking cessation for over a decade since varenicline's approval. There is a crucial need for new approaches and new pharmacotherapy that reduce craving and relapse and can promote sustained abstinence. This application aims to advance the IND development of a novel pharmacotherapeutic with a new first-in-class mechanism for relapse prevention and smoking cessation, that has shown distinctive preclinical efficacy in decreasing cue-induced, stress-induced and nicotine-induced relapse and nicotine self-administration. The lead drug candidate is a new molecular entity targeting a new pharmacological mechanism, the α3β4 nicotinic acetylcholine receptor (nAChR). The α3β4 nAChR clearly plays a role in nicotine dependence and drug relapse mechanisms, and genome-wide association studies in a large population of smokers reveal that polymorphisms in the genes encoding the α3, β4 and α5 subunits of the nAChR are linked to increases in risk for nicotine dependence and inability to quit. The lead candidate proposed for development is selected from a novel series of highly potent and selective α3β4 nAChR ligands, which to our knowledge, are some of the most selective α3β4 nAChR ligands reported. Importantly, their excellent in vivo efficacy for blocking reinstatement of nicotine seeking (a model of relapse), strongly suggests that targeting the α3β4 nAChR may provide a superior profile over existing treatments, particularly for improving longterm abstinence and preventing relapse. We have completed several preclinical toxicology and DMPK studies that confirm the suitability of the lead candidate for IND-enabling studies. We propose to continue the development and file an IND to enable the assessment of the safety and efficacy of this first-in- class mechanism in human clinical trials. With our results thus far, we anticipate that we will be able to advance the future clinical development of this drug candidate into a successful smoking cessation medication and a safe effective option for quitting and sustaining long-term abstinence.