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.

抽象的 该申请是对Par-18-219的响应 物质使用疾病，提出提高新型小分子药物的辅助发展的提议 候选人具有新颖的一流机制，作为戒烟，预防救济的药物治疗 和长期禁欲。初次禁止药物治疗后，人们很常见吸烟非常普遍 并代表了一个主要的临床挑战。所有三种可用药物治疗的24周禁欲率 仍然很差，Varenicline的平均值仅为22％，安非他酮16％，尼古丁替代品的平均值为16％ 疗法，安慰剂为9％。这些与当前药物治疗的禁欲率不佳 鉴于烟草的使用仍然是可预防的领先的烟草危害不足 发达国家的死亡和发病率。尽管有明确的需求和可能的高影响，但 自从Varenicline的' 赞同。对新方法和新的药物疗法至关重要，以减少渴望和 复发，可以促进持续的禁欲。该应用程序旨在提高IND的发展 新颖的药物治疗性，具有新的一流机制，用于预防和戒烟， 在减少提示，应力诱导和尼古丁诱导的方面，这表明了独特的临床前效率 复发和尼古丁自我管理。牵头药物候选人是针对新的新分子实体 药理学机制，α3β4烟碱乙酰胆碱受体（NACHR）。 α3β4NACHR清楚 在尼古丁依赖性和药物继电器机制中起作用，以及全基因组的关联研究 大量吸烟者表明，编码编码α3，β4和α5亚基的基因中的多态性 NACHR与尼古丁依赖性的风险增加和无法戒烟有关。主要候选人 提出的开发是从一系列新型高潜力和选择性α3β4NACHR配体的系列中选择的， 据我们所知，这是报告的一些最选择性的α3β4NACHR配体。重要的是，他们的 强烈建议，优秀的体内效率可阻止恢复尼古丁寻求的恢复（一种救济模型），强烈建议 靶向α3β4NACHR可能比现有处理具有优越的特征，特别是 改善长期禁欲和防止继电器。我们已经完成了几种临床前毒理学和 DMPK研究证实了主要候选人对辅助研究的适用性。我们建议 继续开发并提出IND，以评估该第一届第一届的安全性和效率 人类临床试验中的类机制。到目前为止，我们的结果，我们预计我们将能够 将该候选药物的未来临床发展推向成功的戒烟药物 以及安静和维持长期禁欲的安全有效选择。