Physics

Proof of concept

Internal medicine

Neuroscience

Receptor

Anhedonia

Operating system

Intensive care medicine

Psychology

Randomized controlled trial

Antagonism

Opioid

Computer science

Dopamine

Quantum mechanics

Mechanism (biology)

Medicine

Pharmacology

Nature Medicine

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 &lt; 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. A phase 2 proof-of-mechanism trial shows that a κ-opioid receptor antagonist improves reward-related functioning in the brain and a clinical measure of anhedonia in patients with mood and anxiety disorders, serving as a model for implementing the ‘fast-fail’ approach to psychiatric treatment development.

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