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

开发具有一流戒烟、复吸和戒烟机制的新型候选药物

• 批准号: 9788405
• 负责人: Nurulain T Zaveri
• 金额: $ 215.88万
• 依托单位: ASTRAEA THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788405
• 关键词: Abstinence; Address; Advanced Development; Affinity; Agonist; Analytical Chemistry; Animal Model; Back; Behavioral; Bupropion; Canis familiaris; Cardiovascular system; Cause of Death; Chemicals; Clinical; Clinical Drug Development; Clinical Research; Clinical Trials; Country; Cues; Cyclic GMP; Development; Development Plans; Dose; Drug Kinetics; Exposure to; Formulation; Future; Gene Cluster; Genes; Genetic Polymorphism; Goals; Harm Reduction; Human; Human Genetics; Intake; Investigation; Investigational Drugs; Lead; Legal patent; Ligands; Link; Maintenance; Modeling; Molecular; Monkeys; Morbidity - disease rate; Nicotine; Nicotine Dependence; Nicotinic Receptors; Oral; Outcome; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Placebos; Play; Population; Positioning Attribute; Preparation; Process; Property; Rattus; Relapse; Reporting; Risk; Rodent; Role; Route; Safety; Secure; Self Administration; Series; Small Business Innovation Research Grant; Smoker; Smoking; Smoking Behavior; Solubility; Stress; Substance Use Disorder; Telemetry; Testing; Therapeutic; Tobacco; Tobacco use; Toxicology; Validation; Vomiting; Withdrawal; cardiovascular pharmacology; clinical development; craving; dependence relapse; disorder later incidence prevention; drug candidate; drug discrimination; drug relapse; genetic association; genome wide association study; genotoxicity; improved; in vivo; lead candidate; lead optimization; meetings; method development; nanomolar; nicotine replacement; nicotine seeking behavior; nonhuman primate; novel; novel strategies; novel therapeutics; off-patent; phase I trial; pre-clinical; preclinical efficacy; prevent; respiratory; response; safety assessment; safety study; scale up; small molecule; smoking cessation; success; varenicline

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.

摘要 本申请是对PAR-18-219“药物开发的重大机遇”的回应， 物质使用障碍“，提出推进IND使能开发一种新型小分子药物 候选人与一个新的一流的机制作为药物治疗戒烟，复发预防 长期禁欲。药物治疗戒烟后复吸是很常见的 并且代表了主要的临床挑战。24-所有三种可用药物疗法的一周禁欲率 伐尼克兰平均只有22%，安非他酮平均只有16%，尼古丁替代品平均只有16 与安慰剂相比，安慰剂为9%。目前药物治疗的低戒烟率是 鉴于烟草使用仍然是可预防的主要疾病， 死亡和发病的原因。尽管有明确的需求和可能的高影响， 自从伐尼克兰的戒烟药物上市以来， 批准迫切需要新的方法和新的药物疗法来减少渴望， 复发，可以促进持续的禁欲。该申请旨在推进IND开发， 具有预防复发和戒烟的新机制的新型药物， 其在减少线索诱导的、应激诱导的和尼古丁诱导的 复发和尼古丁自我给药。先导候选药物是一种新的分子实体， 药理学机制，α3β4烟碱乙酰胆碱受体（nAChR）。α3β4 nAChR明显 在尼古丁依赖和药物复发机制中起作用， 大量吸烟者揭示了编码α3、β4和α5亚基基因多态性， 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 从一系列新型高效和选择性α3β4 nAChR配体中选择， 据我们所知，这是一些报道的最具选择性的α3β4 nAChR配体。重要的是他们 阻断尼古丁寻求的恢复（复发模型）的极好的体内功效，强烈表明 靶向α3β4 nAChR可能提供优于现有治疗的上级特征，特别是对于 改善长期戒断和预防复发。我们已经完成了几项临床前毒理学研究， DMPK研究，确认了IND使能研究的主要候选药物的适用性。我们建议 继续开发并提交IND，以评估这种首次临床试验的安全性和有效性。 类机制在人体临床试验。根据我们目前的结果，我们预计我们将能够 推进该候选药物的未来临床开发，使其成为成功的戒烟药物 也是戒烟和维持长期禁欲的安全有效选择。