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

摘要 这项申请是为了响应PAR-19-327‘药物开发的重大机遇 物质使用障碍“，建议推进一种新的戒烟方法的开发 药物治疗进入人类首例(FIH)1期和早期2A期疗效临床试验，随后 我们目前的药物开发项目U01DA047791将于2021年第一季度末提交IND。对此 正在进行的U01项目，Astraea Treeutics推动了一种新型小分子药物的开发 具有针对α3β4烟碱乙酰胆碱的一流药理机制的候选药物 受体(NAChR)亚型。靶向nAChRs，尼古丁成瘾行为的主要靶点，已被证明 是一种成功的临床戒烟方法，以varenicline(ChantixTM)的成功为例， 一种针对α4β2nAchR的部分激动剂。然而，尼古丁依赖的几个方面 人类，特别是节欲比率低和经常复发，目前没有得到很好的解决 药物疗法表明，只有不到一半的吸烟者有戒烟动机，能够通过 治疗结束后，能保持长期戒断(高复发率)的人更少。人类基因 相关性研究表明，其他nAChR亚型，特别是α3β4亚型 与尼古丁依赖的几个方面以及α3、α5基因的多态性相关 和β4nAChRs，与重度吸烟、无法戒烟以及对尼古丁的敏感性增加有关 在禁欲期间。支持这些遗传学发现的是，β4nAChR的功能激活被证明可以恢复 尼古丁奖励的“停止”信号，暗示了阿斯利康显著疗效的耐人寻味的解释 α-3-β-4选择性部分激动剂候选药物在减少大鼠尼古丁自身给药中的作用。甚至更多 重要的是，对药物诱导、应激诱导和线索诱导的恢复的显著抑制 这种先导化合物表现出尼古丁寻求(一种复发的动物模型)，剂量低于 阻止尼古丁摄取是一项新发现，它将这种α3β4选择性候选药物与α4β2区分开来。 选择性药物varenicline，在阻止尼古丁寻求的恢复方面效力较弱或无效 动物复发模型。在复发方面的后一种疗效将Astraea的新方法与varenicline区分开来 和安非他酮，这并不能阻止复发。我们成功地实现了目前药物治疗的所有里程碑 开发项目，还完成了与FDA的IND前会议，以就我们的非临床 支持拟议的临床开发的最终TOX包。这笔赠款的目的是推动 AT-1082在FIH单次和多次递增剂量(SAD/MAD)FIH试验中的临床进展 评估人体的安全性、耐受性和药代动力学(PK)，并进行有效的早期 使用交叉程序的第二阶段试验，将提供吸烟药物疗效的早期读数 停止和通过/不通过的决定，将这一新的一流候选人提升到随后的更大 2期随机试验。该项目拥有一支经验丰富的药物开发团队，已成功 将该项目提交到IND备案，并可以支持拟议的临床开发。如果证明是安全的，那么- 耐受性和有效性，这种候选药物具有潜在的临床特征，可能是 优于现有的戒烟药物系列，可以对 治疗尼古丁成瘾，特别是通过降低复发风险和提高戒烟率。

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.