CERC-501 Kappa Antagonist for Nicotine Dependence

 描述（由申请人提供）：在美国，烟草每年造成的死亡人数超过艾滋病毒、非法药物、酒精、机动车事故和枪支相关死亡人数的总和。虽然戒烟疗法的商业化提高了戒烟率，但长期戒烟率很低。κ阿片受体（KOR）拮抗剂有可能解决与尼古丁戒断相关的情绪变化，包括易怒、焦虑和抑郁。KOR被慢性物质暴露上调，并被认为参与介导应激诱导的药物寻求行为的恢复。迄今为止的数据支持一个新的共识，即KOR拮抗剂具有抗抑郁样作用，减少过量物质消耗，减少药物戒断（尼古丁，酒精，海洛因）的行为和体征。高选择性、口服活性、每日一次、耐受性良好的kappa拮抗剂（如CERC-501）的可用性将代表物质使用障碍（包括尼古丁依赖）的有希望的治疗替代方案。迄今为止的临床研究表明，CERC-501在健康成年人中安全且选择性地阻断KOR。在动物研究中，CERC-501已证明具有抗抑郁样作用，并减少尼古丁戒断大鼠的痛觉过敏、躯体体征和旷场行为。Cerecor的CERC-501计划包括将其注册为戒烟治疗的辅助药物。该提案的主要目的是在1b/2a期人体实验室研究中生成数据，证明CERC-501相对于安慰剂增加了抵抗吸烟的能力，通过非寻求治疗的重度吸烟者的首次吸烟时间和自我吸烟数量进行测量（具体目标1）。本文提出的实验范例先前已由其他人开发和验证（McKee等人，2012; Roche等人，2014），以测量在受控环境中经历戒烟的吸烟者的吸烟失效行为（至第一支香烟的时间;吸烟的香烟数量）。该模型似乎是敏感的“真实的世界”吸烟复发的危险因素，尼古丁依赖的严重程度，以及吸烟的享乐效应的程度。建议健康的重度吸烟者在工作人员观察下每日给予CERC-501至稳态，然后入住临床研究病房进行过夜尼古丁戒断。戒烟18小时后，将向受试者提供吸烟提示，并每5分钟奖励一次戒烟。一旦确定了失效时间，将允许他们随意吸烟。将评估CERC-501对尼古丁戒断、情绪、快感缺乏、焦虑和渴望的状态指标的影响，以及其在该队列中的安全性和耐受性（具体目标2和3）。

 DESCRIPTION (provided by applicant): Tobacco contributes to more deaths in the US each year than HIV, illicit drugs, alcohol, motor vehicle accidents, and firearm-related fatalities combined. While the commercialization of therapies for smoking cessation has enhanced abstinence, long-term abstinence rates are low. Kappa opiate receptor (KOR) antagonism has the potential to address the mood alterations that are associated with nicotine withdrawal, including irritability, anxiety, and depression. KORs are upregulated by chronic substance exposure and are thought to participate in mediating stress-induced reinstatement of drug-seeking behavior. Data to date support an emerging consensus that KOR antagonists have antidepressant-like effects, reduce excessive substance consumption, and reduce behaviors and signs of drug withdrawal (nicotine, alcohol, heroin). The availability of a highly selective, orally active, once-daily, well-tolerated kappa antagonist like CERC-501 would represent a promising treatment alternative for substance use disorders including nicotine dependence. Clinical studies to date suggest that CERC-501 safely and selectively blocks KOR in healthy adult humans. In animal studies, CERC-501 has demonstrated antidepressant-like effects and reduces the hyperalgesia, somatic signs and open field behaviors of nicotine-withdrawn rats. Cerecor's plans for CERC-501 include its registration as an aid to smoking cessation treatment. The primary objective of the proposal is to generate data in a Phase 1b/2a human laboratory study demonstrating that CERC-501 increases the ability to resist smoking relative to placebo, as measured by time to first cigarette and number of self-administered cigarettes in non-treatment seeking heavy smokers (Specific Aim 1). The experimental paradigm proposed herein has been previously developed and validated by others (McKee, et al 2012; Roche, et al 2014) to measure smoking lapse behaviors (time to first cigarette; number of cigarettes smoked) in smokers undergoing abstinence from cigarette smoking in a controlled environment. The model appears to be sensitive to risk factors for `real world' smoking relapse, the severity of nicotine dependence, and the degree of hedonic effect achieved with smoking. Healthy, heavy smokers are proposed to be dosed under staff observation daily with CERC-501 to steady state, and then admitted to a clinical research ward for overnight nicotine abstinence. After 18 hours of abstinence, the subjects will be presented with a smoking cue, and rewarded for every 5 minutes that they are able to abstain from smoking. Once the time to lapse has been established, they will be allowed to smoke ad libitum. The impact of CERC-501 on state measures of nicotine withdrawal, mood, anhedonia, anxiety, and craving, as well as its safety and tolerability in this cohort will be assessed (Specific Aims 2 and 3).