| Literature DB >> 32231295 |
Andrew D Krystal1,2, Diego A Pizzagalli3, Moria Smoski4, Sanjay J Mathew5,6, John Nurnberger7, Sarah H Lisanby8, Dan Iosifescu9, James W Murrough10, Hongqiu Yang11, Richard D Weiner4, Joseph R Calabrese12, Gerard Sanacora13, Gretchen Hermes13, Richard S E Keefe4, Allen Song4, Wayne Goodman5, Steven T Szabo4,14, Alexis E Whitton3,15, Keming Gao12, William Z Potter8.
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, 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.Entities:
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Year: 2020 PMID： 32231295 DOI： 10.1038/s41591-020-0806-7
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440