Medication development of a novel therapeutic for smoking cessation

描述(由申请者提供)：近5000万美国人吸烟，这是全球主要的可预防的死亡原因。尽管大多数人报告想戒烟，但很少有人在给定的戒烟尝试中成功，即使在目前可用的治疗方法下也是如此。在过去30年中，在数十种用于戒烟的临床试验中，只有3种药物获得了FDA的批准(尼古丁替代品、varenicline、安非他酮)。需要更多有效的药物来帮助大多数依赖吸烟者成功永久戒烟。该应用程序使用简化的两阶段方法来评估一种新化合物作为戒烟药物的有效性。在第一阶段，将根据非常令人信服的啮齿动物模型的初步数据进行临床前可行性研究，这些啮齿动物模型是人类戒烟药物的有效预测因子。随后将进行第二阶段的人类临床2a期研究，以寻找戒烟疗效的药物证据。药物戒断和安慰剂禁欲将在一个经过充分验证的创新程序中进行比较，以进行最初的疗效测试。我们还将评估这种药物逆转戒断症状的机制。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疗效。此外，这一应用程序的一个极具创新性的部分是在更广泛的健康依赖型吸烟者和患有精神分裂症的吸烟者中测试戒烟的药物疗效，这些吸烟者吸烟率很高，但戒烟的治疗选择有限。鉴于研究人员进行非常相似的临床前和临床研究的丰富经验，这项研究的可行性是巨大的。这一应用的结果可能导致一种治疗尼古丁依赖的新药，降低公共卫生的巨大成本，并可能为最脆弱的吸烟者提供第一种有效的戒烟方法。

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.