Medication development of a novel therapeutic for smoking cessation

描述（由申请人提供）：近5000万美国人吸烟，这是世界上可预防的主要死亡原因。尽管大多数人报告想要戒烟，但即使使用目前可用的治疗方法，在给定的戒烟尝试中也很少有人成功。在过去的30年里，在临床试验中用于戒烟的几十种药物中，只有3种得到了FDA的批准（尼古丁替代品，伐尼克兰，安非他酮）。需要额外的有效药物来帮助大多数依赖吸烟者成功永久戒烟。这个应用程序使用一个精简的两阶段的方法来评估一个新的化合物作为戒烟药物的功效。在第一阶段，临床前可行性研究将基于高度令人信服的啮齿动物模型的初步数据进行，这些数据已被证实是人类戒烟药物的预测指标。随后将进行第二阶段的人体临床2a期研究，以检测戒烟疗效的药物证据。由于药物和安慰剂引起的禁欲将在一个经过充分验证的创新程序中进行疗效的初步测试。我们还将评估这种药物逆转禁欲症状的机制。这些临床研究受益于受试者内交叉设计，作为一种高通量方法，以高效的方式预测戒烟药物的治疗效果。此外，该应用程序的一个高度创新的组成部分是在更广泛的健康依赖吸烟者人群和患有精神分裂症的吸烟者中测试戒烟的药物功效，他们的吸烟率非常高，但戒烟的治疗选择有限。考虑到研究人员在进行非常相似的临床前和临床研究方面的丰富经验，这项研究的可行性是实质性的。这项应用的结果可能会导致一种治疗尼古丁依赖的新药，减少公共卫生的巨大成本，并可能为最脆弱的吸烟者戒烟提供第一个有效的治疗方法。

DESCRIPTION (provided by applicant): Nearly 50 million Americans smoke cigarettes, the leading preventable cause of death worldwide. Although most report wanting to quit, few are successful during a given quit attempt even with currently available therapeutics. Of dozens of drugs tested in clinical trials for cessation over the last three decades, only 3 have been approved by the FDA (nicotine replacement, varenicline, bupropion). Additional effective medications are needed to help the majority of dependent smokers succeed in quitting permanently. This application uses a streamlined two-stage approach to evaluate the efficacy of a new compound as a medication for smoking cessation. In the first stage, preclinical feasibility studies will be performed based on highly convincing preliminary data in rodent models that are validated predictors of medications for smoking cessation in humans. These will be followed by the second stage, human clinical Phase 2a studies to detect medication evidence of efficacy for smoking cessation. Abstinence due to medication versus placebo will be compared within a well-validated, innovative procedure for initial test of efficacy. We will also assess the mechanisms through which this medication reverses symptoms of abstinence. These clinical studies benefit from a within- subject crossover design as a high throughput method for predicting therapeutic efficacy of smoking cessation drugs in a highly efficient manner. Moreover, a highly innovative component of this application is to test medication efficacy for smoking cessation in both the broader population of healthy dependent smokers and in smokers with schizophrenia, who have very high rates of smoking but limited therapeutic alternatives to quit smoking. The feasibility of this research is substantial, given the investigators' extensive experience conducting very similar preclinical and clinical research. Results of this application could lead to a new medication to treat nicotine dependence, reducing enormous costs to public health and providing perhaps the first effective treatment for cessation in the most vulnerable smokers.