Target Engagement and Clinical Symptom Change with a FAAH Inhibitor for Posttraumatic Stress Disorder

迫切需要基于机制的新的药理学方法来治疗创伤相关的 创伤后应激障碍(PTSD)等障碍，因为40%-60%的患者对目前的 药物或行为疗法。创伤后应激障碍症状模式和轨迹的高度异质性 表明多种神经生物系统发生了变化。负向效价加工与反应中的唤醒 对情感刺激(AS)和条件性恐惧刺激(CFS)的研究被认为是多水平的翻译 NIMH研究领域标准(RDoC)中与创伤和其他应激相关的过程- 相关的障碍。已经观察到大脑系统的功能受到可靠的干扰，这些系统调节 以及创伤后应激障碍患者的CFS反应性。一类作用于内源性大麻系统的药物， 脂肪酸酰胺水解酶抑制剂(FAAHi)是基于大量临床前研究的假设。 研究，以调节AS和CFS监管系统中的活动(例如，增强恐惧消退)。FAAHi 因此可为创伤后应激障碍患者提供临床益处--并可跨诊断为其他焦虑和 与应激源相关的情况--在这些回路中表现出持续的功能障碍。建议的项目评估 由JNJ-42165279 Janssen开发和表征的FAAHi的能力，以使用以下系统 调节AS(例如，情绪面孔加工过程中杏仁核的激活；主要目标)和CFS(例如，恐惧 消退；次要目标)，以减少过度觉醒(主要临床结果)和重新 出现症状(次要结果)。该项目的目标得到了大量的初步数据的支持。 健康人体表明JNJ-42165279呈剂量依赖关系抑制FAAH，剂量-效应关系 血浆ANANDAME的依赖性增加；FAAH的饱和度(&gt；80%)在没有 临床上对人类有显著的不良影响；一旦达到稳定状态，AS和CFS的反应性 衰减了。基于这些观察，我们提出了一种两点随机双盲固定剂量(25 mg JNJ-42165279在N=150名创伤后应激障碍患者中的安慰剂对照试验。目标1寻求确认目标 AS处理过程中杏仁核激活的减少(主要靶点)以及减少 在创伤叙述和恐惧消退回忆中暴露的生理和主观CFS反应 (次级指标)从基线到稳定状态(治疗5天)。目标2将检验这一假设 在JNJ-42165279组中，从基线到第5天杏仁核反应性的减弱将与 从基线到第8周的症状变化。我们将探索次要指标变化之间的联系 目标参与(创伤特有的唤醒反应和恐惧消退回忆)与过度唤醒的变化 并在8周时再次出现症状。如果这些预测得到证实，这个项目将支持未来 FAAHi(和其他具有类似作用机制的药物)在确定性、大范围随机对照中的研究 创伤后应激障碍和其他焦虑和应激源相关疾病在AS和CFS领域的功能障碍试验。

There is an urgent need for mechanism-based novel pharmacological approaches to treat trauma-related disorders such as posttraumatic stress disorder (PTSD), as 40-60% of patients do not respond to current pharmacological or behavioral therapies. High heterogeneity of symptom patterns and trajectories in PTSD suggests alterations in multiple neurobiological systems. Negative valence processing and arousal in response to affective stimuli (AS) and conditioned fear stimuli (CFS) have been proposed as translational multi-level processes within the NIMH Research Domain Criteria (RDoC) that are relevant to trauma and other stress- related disorders. Reliable disruptions have been observed in the functioning of brain systems that regulate AS and CFS reactivity in individuals with PTSD. A class of medications acting on the endocannabinoid system, inhibitors of fatty acid amide hydrolase (FAAHi) are hypothesized, based on a large body of preclinical research, to modulate activity in AS and CFS regulatory systems (e.g., enhancement of fear extinction). FAAHi may therefore offer clinical benefit for patients with PTSD—and trans-diagnostically for other anxiety and stressor-related conditions—who show consistent dysfunction in those circuits. The proposed project evaluates the ability of a FAAHi developed and characterized by Janssen, JNJ-42165279, to engage systems that regulate AS (e.g., amygdala activation during emotion face processing; primary target) and CFS (e.g., fear extinction; secondary target) in the service of reducing hyperarousal (primary clinical outcome) and re- experiencing symptoms (secondary outcome). The project aims are supported by extensive preliminary data in healthy humans indicating that JNJ-42165279 dose-dependently inhibits FAAH as evidenced by dose- dependent increases in plasma anandamide; saturation of FAAH (>80%) is achieved at doses that have no clinically significant adverse effects in humans; and once steady state is achieved, AS and CFS reactivity is attenuated. Based on these observations, we propose a two-site, randomized double-blind fixed dose (25 mg BID) placebo-controlled trial of JNJ-42165279 in N=150 patients with PTSD. Aim 1 seeks to confirm target engagement through reduced amygdala activation during AS processing (primary target) as well as reduced physiological and subjective CFS reactivity during exposure to a trauma narrative and fear extinction recall (secondary targets) from baseline to steady state (5 days of treatment). Aim 2 will test the hypothesis that attenuation of amygdala reactivity from baseline to Day 5 in the JNJ-42165279 group will be associated with symptom change from baseline to week 8. We will explore links between changes in secondary measures of target engagement (trauma-specific arousal reactivity and fear extinction recall) and changes in hyperarousal and re-experiencing symptoms at 8 weeks. If these predictions are confirmed, this project will support future studies of FAAHi (and other drugs with similar mechanisms of action) in definitive, larger randomized controlled trials for PTSD and other anxiety and stressor-related conditions with dysfunction in AS and CFS domains.