A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.
Nat Med
; 26(5): 760-768, 2020 05.
Article
in En
| MEDLINE
| ID: mdl-32231295
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:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrrolidines
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Benzamides
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Receptors, Opioid, kappa
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Mood Disorders
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Anhedonia
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Narcotic Antagonists
Type of study:
Clinical_trials
/
Prognostic_studies
Limits:
Adult
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Female
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Humans
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Male
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Middle aged
Language:
En
Journal:
Nat Med
Journal subject:
BIOLOGIA MOLECULAR
/
MEDICINA
Year:
2020
Document type:
Article
Affiliation country:
United States
Country of publication:
United States