A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.

Journal Article (Journal Article;Multicenter Study)

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, 10 mg; 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.

Full Text

Duke Authors

Cited Authors

  • Krystal, AD; Pizzagalli, DA; Smoski, M; Mathew, SJ; Nurnberger, J; Lisanby, SH; Iosifescu, D; Murrough, JW; Yang, H; Weiner, RD; Calabrese, JR; Sanacora, G; Hermes, G; Keefe, RSE; Song, A; Goodman, W; Szabo, ST; Whitton, AE; Gao, K; Potter, WZ

Published Date

  • May 2020

Published In

Volume / Issue

  • 26 / 5

Start / End Page

  • 760 - 768

PubMed ID

  • 32231295

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/s41591-020-0806-7


  • eng

Conference Location

  • United States