美国加州大学Andrew D. Krystal小组的一项最新研究，揭示了一项采用“快速失败”方法评估κ阿片类药物拮抗作用的随机机制验证试验。2020年3月30日，《自然—医学》在线发表了这项成果。

研究人员报告了一项在患有快感缺乏症和情绪焦虑症（选择性KOR拮抗剂<JNJ-67953964，10 mg； n = 45>），安慰剂（n = 44））病人中进行的多中心、为期8周、双盲、安慰剂对照、随机试验的结果。

与安慰剂相比，JNJ-67953964在奖励预期（主要结果）期间显着增加了功能性磁共振成像（fMRI）腹侧纹状体的激活（基线调整后的平均值：JNJ-67953964，0.72<标准差= 0.67>；安慰剂0.33<标准差= 0.68> ）; F（1,86）= 5.58，P <0.01;效应大小= 0.58（95％置信区间，0.13–0.99）。耐受范围内使用JNJ-67953964与任何严重的副反应无关。这项研究支持对潜在靶点的临床应用进行评估，并可作为使用“快速失败”方法的模型。

据介绍，美国国家心理健康研究所（NIMH）的“快速失败”方法旨在通过在2a期临床中采用基于生物标记物的机制验证（POM）测试，来改善早期药物开发中经常存在的误判。快速失败方法的首次全面应用是评估κ阿片受体（KOR）拮抗剂治疗快感缺乏症的潜能，利用POM研究确定潜在靶标参与是否会有利地影响脑电路，而脑电路被认为介导了临床作用。

附：英文原文

Title: A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia

Author: Andrew D. Krystal, Diego A. Pizzagalli, Moria Smoski, Sanjay J. Mathew, John Nurnberger, Sarah H. Lisanby, Dan Iosifescu, James W. Murrough, Hongqiu Yang, Richard D. Weiner, Joseph R. Calabrese, Gerard Sanacora, Gretchen Hermes, Richard S. E. Keefe, Allen Song, Wayne Goodman, Steven T. Szabo, Alexis E. Whitton, Keming Gao, William Z. Potter

Issue&Volume: 2020-03-30

Abstract: The National Institute of Mental Health (NIMH) ‘fast-fail’ approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10mg; n=45) and placebo (n=44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d.=0.67); placebo, 0.33 (s.d.=0.68); F(1,86)=5.58, P<0.01; effect size=0.58 (95% confidence interval, 0.13–0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the ‘fast-fail’ approach.

DOI: 10.1038/s41591-020-0806-7

Source: https://www.nature.com/articles/s41591-020-0806-7