First-in-Human Clinical Development of a Novel Drug Candidate with a First-in-Class Mechanism for Smoking Cessation and Abstinence

摘要 本申请是对PAR-19-327“药物开发的重大机遇”的回应， 物质使用障碍“，建议推进一种新型戒烟的发展 药物治疗进入首次人体（FIH）I期和早期2A期疗效临床试验， IND将于2021年第1季度末提交，涉及我们当前的药物开发项目U 01 DA 047791。On this 正在进行的U 01项目，Astraea Therapeutics推进了一种新型小分子的IND开发 具有一流药理学机制的候选药物，靶向α3β4烟碱乙酰胆碱 nAChR亚型。靶向nAChR，尼古丁成瘾作用的主要靶点，已被证明 是一种成功的戒烟临床方法，以伐尼克兰（ChantixTM）的成功为例， 靶向α4β2 nAChR的nAChR部分激动剂。然而，尼古丁依赖的几个方面， 人类，特别是不良的戒断率和频繁复发， 药物治疗，表明只有不到一半的吸烟者有戒烟的动机，能够做到这一点， 治疗结束后，能保持长期戒断的就更少了（复发率高）。人类遗传 相关研究表明，其他nAChR亚型，特别是α3β4亚型， 与尼古丁依赖的几个方面相关，α3，α5 和β4 nAChRs与重度吸烟、无法戒烟和对尼古丁敏感性增加有关 在禁欲期间支持这些遗传学发现，β4 nAChR的功能激活被证明可以恢复 尼古丁奖励的“停止”信号，这对Astraea的显著功效提出了一个有趣的解释。 α3β4选择性部分激动剂候选药物减少大鼠尼古丁自我给药。更 重要的是，药物诱导的，应激诱导的和线索诱导的恢复的显著抑制， 尼古丁寻求（复发的动物模型）显示，这种先导化合物的剂量低于 阻断尼古丁摄入是一项新的发现，它将这种α3β4选择性候选药物与α4β2- 选择性药物伐伦克林，这是不太有效或无效，在阻止恢复尼古丁寻求， 动物复发模型。后一种治疗复发的疗效使Astraea的新方法有别于伐尼克兰 和安非他酮，它们不能阻止复发。我们成功地实现了我们目前药物的所有里程碑 开发项目，并已完成与FDA的preIND会议，以就我们的非临床研究达成一致。 确定的Tox包，以支持拟定的临床开发。该补助金的目的是促进 AT-1082在I期单次和多次递增剂量（SAD/MAD）FIH试验中的临床开发， 评估在人体中的安全性、耐受性和药代动力学（PK）特征，并进行有效的早期 使用交叉程序的II期试验，将提供吸烟药物疗效的早期读数 停止和去/不去的决定，以推动这一新的一流的候选人，以随后更大的 2期随机试验。该项目拥有一支经验丰富的药物开发团队， 将该项目推进至IND备案，并可支持拟定的临床开发。如果证明是安全的，那么- 耐受性和有效性，这种候选药物具有临床特征的潜力， 上级于现有的戒烟药物，并能对吸烟者产生真实的影响。 尼古丁成瘾的治疗，特别是通过降低复发的风险和提高戒烟率。

ABSTRACT This application, in response to PAR-19-327 ‘Grand Opportunity in Medications Development for Substance-use Disorders’, proposes to advance the development of a novel smoking cessation pharmacotherapy into first-in-human (FIH) Phase 1 and early Phase 2A efficacy clinical trials, subsequent to an IND to be filed by end of Q1 of 2021, on our current medication development project U01DA047791. On this ongoing U01 project, Astraea Therapeutics advanced the IND-enabling development of a novel small-molecule drug candidate with a first-in-class pharmacological mechanism targeting the α3β4 nicotinic acetylcholine receptor (nAChR) subtype. Targeting nAChRs, the primary target for nicotine’s addictive actions, has proven to be a successful clinical approach for smoking cessation, exemplified by the success of varenicline (ChantixTM), a nAChR partial agonist targeted to the α4β2 nAChR. However, several aspects of nicotine dependence in humans, particularly poor abstinence rates and frequent relapse, are poorly addressed by current pharmacotherapy, indicated by the fact that fewer than half of smokers motivated to quit, are able to do so by the end of treatment, and even fewer can maintain long-term abstinence (high rate of relapse). Human genetic association studies have shown that other nAChR subtypes, especially the α3β4 subtype is strongly correlated with several aspects of nicotine dependence and that polymorphisms in the genes for the α3, α5 and β4 nAChRs, are associated with heavy smoking, inability to quit, and increased sensitivity to nicotine during abstinence. Supporting these genetic findings, functional activation of β4 nAChR was shown to restore a ‘stop’ signal on nicotine reward, suggesting an intriguing explanation for the remarkable efficacy of Astraea’s α3β4-selective partial agonist drug candidate in decreasing nicotine self-administration in rats. Even more importantly, the significant inhibition of drug-induced, stress-induced and cue-induced reinstatement of nicotine-seeking (an animal model of relapse) shown by this lead compound at doses lower than those blocking nicotine intake is a novel finding that distinguishes this α3β4-selective drug candidate from the α4β2- selective drug varenicline, which is less potent or inactive in blocking reinstatement to nicotine seeking in animal relapse models. This latter efficacy in relapse differentiates Astraea’s novel approach from varenicline and bupropion, which do not block relapse. We successfully achieved all milestones on our current medication development project and have also completed a preIND meeting with the FDA for agreement on our nonclinical definitive Tox package to support the proposed clinical development. The objective of this grant is to advance the clinical development of AT-1082 in Phase 1 single- and multiple-ascending dose (SAD/MAD) FIH trials to assess the safety, tolerability and pharmacokinetic (PK) profile in humans, and to conduct an efficient Early Phase 2 trial using a crossover procedure that will provide an early readout of medication efficacy for smoking cessation and a Go/No-go decision to advance this novel first-in-class candidate to subsequent larger randomized Phase 2 trials. The project has an experienced drug development team that has successfully advanced this project to IND filing and can support the proposed clinical development. If proven safe, well- tolerated and efficacious, this drug candidate has the potential for a clinical profile that could possibly be superior to the existing repertoire of smoking cessation medications and can make a real impact on the treatment of nicotine addiction, particularly by reducing the risk of a relapse and improving abstinence rates.