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 该申请是针对19-327帕尔（Pars）的巨大机会开发药物开发的巨大机会 药物使用障碍的提议提出了一种新型戒烟的发展 在第一阶段（FIH）的药物治疗1和2A早期有效的临床试验，此后 一个IND将在2021年第1季度末提交，这是我们当前的药物开发项目U01DA047791。因此 正在进行的U01项目，Astraea Therapeutics推进了一种新型小分子的成熟开发 具有针对α3β4烟碱乙酰胆碱的第一类药理机制的候选药物 受体（NACHR）亚型。针对NACHR是尼古丁添加剂作用的主要目标，已证明 成为一种成功的临床戒烟方法，以Varenicline（ChantixTM）的成功为例， 针对α4β2NACHR的NACHR部分激动剂。但是，尼古丁依赖性的几个方面 人类，尤其是禁欲率较差和经常缓解的人，当前的解决方案很差 药物疗法表明，只有不到一半的吸烟者戒烟，就可以通过 治疗的终结，甚至更少可以维持长期禁欲（退休率很高）。人类通用 关联研究表明，其他NACHR亚型，尤其是α3β4亚型强烈 与尼古丁依赖性的几个方面以及α3基因中的多态性相关 和β4NACHR与大量吸烟，无法戒烟以及对尼古丁的敏感性有关 戒酒期间。支持这些遗传发现，β4NACHR的功能激活显示为恢复 尼古丁奖励的“停止信号”，这暗示了对Astraea的非凡效率的有趣解释 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，对药物诱导的，应激诱导和提示诱导的重新定位的显着抑制作用 该铅化合物以低于那些的剂量显示的尼古丁寻求尼古丁（退休动物模型） 阻断尼古丁的摄入是一个新颖的发现，将这种α3β4选择性药物候选者与α4β2--区分开 选择性药物变元线，在阻止恢复到尼古丁寻求的情况下的效力较小或不活动 动物救济模型。后来的救济有效性将Astraea的新方法与Varenicline区分开 和安非他酮，不会阻止救济。我们成功地实现了当前药物的所有里程碑 开发项目，还完成了与FDA的预告片会议 确定的TOX软件包，以支持拟议的临床开发。这笔赠款的目的是促进 AT-1082在第1阶段单次和多重剂量（SAD/MAD）FIH试验中的临床开发 评估人类中的安全性，耐受性和药代动力学（PK）剖面，并提早进行有效的早期 使用交叉程序的2阶段试验将提供吸烟的药物效率的早期读数 停止和无行决定，将这位小说的第一类候选人推向随后的较大 随机2期试验。该项目有一个经验丰富的药物开发团队 提出了该项目的提交，并可以支持拟议的临床开发。如果被证明是安全的，那么 该药物候选者的耐受性有效，具有可能是临床特征的潜力 优于现有的戒烟药物的现有曲目，可以对 尼古丁成瘾的治疗，特别是通过降低缓解风险和提高禁欲的风险。