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

具有一流戒烟和节欲机制的新候选药物的首次人体临床开发

• 批准号: 10620310
• 负责人: KENNETH Alan PERKINS
• 金额: $ 139.88万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620310
• 关键词: Abstinence; Address; Adult; Advanced Development; Affinity; Agonist; Agreement; Animal Model; Animals; Brain; Bupropion; CYP2D6 gene; Canis familiaris; Cardiovascular system; Clinical; Clinical Trials; Cues; Cyclic GMP; Dependence; Depressed mood; Development; Digit structure; Dose; Double-Blind Method; Drug Addiction; Drug Kinetics; Food; Formulation; Gene Cluster; Genes; Genetic; Genetic Polymorphism; Goals; Grant; Habits; Human; Human Genetics; In Vitro; Intake; Investigation; Lead; Life Style; Ligands; Link; Modeling; Morbidity - disease rate; Nicotine; Nicotine Dependence; Nicotinic Receptors; Oral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase II Clinical Trials; Phenotype; Placebo Control; Placebos; Play; Procedures; Psychological reinforcement; Randomized; Rattus; Relapse; Reporting; Research Personnel; Risk Reduction; Role; Safety; Sampling; Scientist; Sensitivity and Specificity; Series; Signal Transduction; Smoker; Smoking; Smoking Behavior; Smoking Cessation Intervention; Stress; Substance Use Disorder; Therapeutic; Time; Tobacco; Toxicology; Withdrawal; Writing; capsule; clinical development; clinical investigation; cohort; design; drug candidate; drug development; efficacy clinical trial; electronic cigarette use; experience; first-in-human; genetic association; genotoxicity; improved; in vivo; interest; long term abstinence; meetings; multidisciplinary; nanomolar; nicotine reward; nicotine seeking behavior; nicotine self-administration; nicotine treatment; novel; novel strategies; novel therapeutics; pharmacologic; phase 2 study; phase I trial; phase II trial; preventable death; product development; prolonged abstinence; randomized, clinical trials; relapse prevention; relapse risk; respiratory; response; safety assessment; small molecule; smoking abstinence; smoking addiction; smoking cessation; success; tobacco products; varenicline

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.

抽象的 本申请响应 PAR-19-327“药物开发的巨大机遇” 物质使用障碍”，提议推进新型戒烟方法的开发 药物治疗进入首次人体 (FIH) 1 期和早期 2A 期疗效临床试验，随后 将于 2021 年第一季度末提交关于我们当前药物开发项目 U01DA047791 的 IND。 正在进行的 U01 项目中，Astraea Therapeutics 推进了一种新型小分子的 IND 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 已证明，针对尼古丁成瘾作用的主要目标 nAChR 受体（nAChR）亚型。 成为一种成功的戒烟临床方法，伐尼克兰 (ChantixTM) 的成功就是例证， 一种针对 α4β2 nAChR 的 nAChR 部分激动剂 然而，尼古丁依赖的几个方面。 人类的问题，尤其是低戒断率和频繁复发的问题，目前的治疗方法并没有得到很好的解决。 药物治疗，事实表明，只有不到一半有戒烟动机的吸烟者能够通过以下方式做到这一点： 治疗结束时，能保持长期戒断的就更少了（复发率高是人类遗传的）。 关联研究表明，其他 nAChR 亚型，尤其是 α3β4 亚型强烈 与尼古丁依赖的几个方面以及 α3、α5 基因的多态性相关 和 β4 nAChR，与大量吸烟、无法戒烟和对尼古丁的敏感性增加有关 在禁欲期间，β4 nAChR 的功能激活被证明可以恢复。 尼古丁奖励的“停止”信号，为 Astraea 的卓越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可减少大鼠的尼古丁自我给药。 显着地，显着抑制药物诱导、应激诱导和提示诱导的恢复 该先导化合物在剂量低于这些剂量时表现出尼古丁寻求（复发的动物模型） 阻止尼古丁摄入是一项新颖的发现，它将这种 α3β4-选择性候选药物与 α4β2- 选择性药物伐尼克兰，其在阻止尼古丁恢复方面效力较弱或无活性 动物复发模型中的后者对复发的功效使 Astraea 的新方法与伐尼克兰区分开来。 和安非他酮，它们不能阻止复发。我们成功实现了当前药物治疗的所有里程碑。 开发项目，还完成了与 FDA 的 preIND 会议，就我们的非临床达成一致 支持拟议临床开发的最终 Tox 方案 这笔赠款的目的是推进。 AT-1082 在 1 期单次和多次递增剂量 (SAD/MAD) FIH 试验中的临床开发 评估人类的安全性、耐受性和药代动力学 (PK) 特征，并进行有效的早期研究 使用交叉程序的第 2 期试验将提供吸烟药物疗效的早期读数 停止和继续/不继续决定将这个新颖的一流候选者推进到后续更大的 该项目拥有一支经验丰富的药物开发团队，已成功进行了随机 2 期试验。 该项目已提交 IND 申请，如果被证明是安全的，可以支持拟议的临床开发。 该候选药物具有耐受性和有效性，具有潜在的临床特征 优于现有的戒烟药物，可以对戒烟产生真正的影响 治疗尼古丁成瘾，特别是通过降低复发风险和提高戒烟率。