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

Nature medicine, 2020-05, Vol.26 (5), p.760 [Peer Reviewed Journal]

COPYRIGHT 2020 Nature Publishing Group ;COPYRIGHT 2020 Nature Publishing Group ;ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/s41591-020-0806-7

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  • Title:
    A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating [kappa]-opioid antagonism as a treatment for anhedonia
  • Author: Krystal, Andrew D ; Pizzagalli, Diego A ; Smoski, Moria ; Mathew, Sanjay J ; Nurnberger, John, Jr ; Lisanby, Sarah H ; Iosifescu, Dan
  • Subjects: Anhedonia ; Care and treatment
  • Is Part Of: Nature medicine, 2020-05, Vol.26 (5), p.760
  • Description: 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 [kappa]-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.
  • Publisher: Nature Publishing Group
  • Language: English
  • Identifier: ISSN: 1078-8956
    EISSN: 1546-170X
    DOI: 10.1038/s41591-020-0806-7
  • Source: ProQuest Central
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