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.
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Study data have been posted to the NIH/NIMH data archive and are accessible by emailing NDAHelp@mail.nih.gov.
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Acknowledgements
This project was supported by contract HHS-N271-2012-000006-I from the National Institute of Mental Health awarded to A.D.K. D.A.P. was partially supported by R37 MH068376. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the US government.
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A.D.K. designed the study, provided oversight for all aspects of the study, analyzed the data and wrote the manuscript. W.Z.P. provided critical intellectual input for designing the study and contributed to writing the manuscript. D.A.P. provided critical intellectual input for designing the study, provided training, oversight and data analysis for the aspects of the study related to the behavioral tests, and co-wrote the manuscript. A.E.W. provided training, oversight and data analysis for the aspects of the study related to the behavioral tests. S.J.M., S.H.L., J.R.C., G.S. and W.G. contributed to designing the study, provided oversight for a study site where they led efforts in training and managing study personnel, recruiting participants and completing all protocol-specified study procedures including data collection with the participants, and contributed to writing the manuscript. R.D.W. and J.N. provided oversight for a study site where they led efforts in training and managing study personnel, recruiting participants and completing all protocol-specified study procedures including data collection with the participants and contributed to writing the manuscript. A.S. and M.S. provided oversight for collection and analysis of the MRI data and contributed to writing the manuscript. H.Y. served as statistician for the study, contributing to study design, carrying out data analysis and contributing to writing the manuscript. R.S.E.K. contributed to designing the study, provided data quality oversight and contributed to writing the manuscript. D.I., S.T.S., G.H. and K.G. participated in recruiting participants, completing all protocol-specified study procedures including data collection with the participants, and contributed to writing the manuscript.
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A.D.K. has been a consultant for Adare, Eisai, Ferring, Galderma, Idorsia, Jazz, Janssen, Takeda, Merck, Neurocrine, Pernix, Physician’s Seal, Evecxia and Sage Research and received support from the NIH, the Ray and Dagmar Dolby Family Fund, Janssen, Jazz. Axsome and Reveal Biosensors. D.A.P. has consulted for Akili Interactive Labs, BlackThorn Therapeutics, Boehringer Ingelheim, Compass Pathway, Otsuka Pharmaceuticals, Posit Science and Takeda Pharmaceuticals and received honoraria from Alkermes. D.A.P. has a financial interest in BlackThorn Therapeutics, which has licensed the copyright to the PRT through Harvard University. The interests of D.A.P. were reviewed and are managed by McLean Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. S.J.M. has been a consultant for Allergan, Alkermes, Greenwich Biosciences, Clexio Biosciences, Intra-Cellular Therapies, Janssen, Perception Neuroscience, Sage Therapeutics, Signant Health and Seelos Therapeutics and received research support from Biohaven, Janssen, the NIH, NeuroRx and VistaGen Therapeutics, drug from Biohaven for NIMH-funded study and support from the Michael E. Debakey VA Medical Center (Houston, TX) for use of resources and facilities. G.S. has consulted for Allergan, Alkermes, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Clexio Biosciences, EMA-Wellness, Hoffman La-Roche, Intra-Cellular Therapies, Janssen, Merck, Naurex, Navitor Pharmaceuticals, Novartis, Noven Pharmaceuticals, Otsuka, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant and Vistagen Therapeutics and received research funding from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck, Naurex and Servier. G.S. has equity interests in Biohaven Pharmaceuticals and receives patent royalties from Biohaven. J.W.M. has consulted for Boehringer Ingelheim, Sage Therapeutics, Novartis, Allergan, Fortress Biotech, Janssen Research and Development, Medavante-Prophase and Global Medical Education (GME) and received research support from Avanir Pharmaceuticals. R.S.E.K. has consulted for or been a speaker or advisory board member for Abbvie, Acadia, Aeglea, Akebia, Akili, Alkermes, Allergan, ArmaGen, Astellas, Avanir, Axovant, Biogen, Boehringer Ingelheim, Cerecor, CoMentis, Critical Path Institute, FORUM, Gammon Howard & Zeszotarski, Global Medical Education (GME), GW Pharmaceuticals, Intracellular Therapeutics, Janssen, Kempharm, Lundbeck, Lysogene, MedScape, Mentis Cura, Merck, Merrakris Therapetics, Minerva Neurosciences, Mitsubishi, Montana State University, Monteris, Moscow Research Institute of Psychiatry, Neuralstem, Neuronix, Novartis, the New York State Office of Mental Health, Orygen, Otsuka, Paradigm Testing, Percept Solutions, Pfizer, Pharm-Olam, Regenix Bio, Reviva, Roche, Sangamo, Sanofi, SOBI, Six Degrees Medical, Sunovion, Takeda, Targacept, Teague Rotenstreich Stanaland Fox & Holt, Thrombosis Research Institute, the University of Moscow, the University of Southern California, the University of Texas Southwestern Medical Center, WebMD and Wilson Therapeutics. R.S.E.K. has received research funding from the National Institute of Mental Health and Boehringer Ingelheim and royalties from Versions of the BAC testing battery, the MATRICS Battery (BACS Symbol Coding) and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). R.S.E.K. is a shareholder in VeraSci and Sengenix. S.H.L. contributed to this article while at Duke University, before joining the National Institute of Mental Health. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health or the US government. S.H.L. is a co-inventor on a patent for TMS Technology, unrelated to this manuscript. J.N. has received research funding from Janssen and Assurex. A.S. has received research support from the NIH and GE Healthcare. W.G. has consulted for Biohaven Pharmaceuticals and received research funding from the NIH, the Simons Foundation and Biohaven Pharmaceuticals Device Donation: Medtronic. S.T.S. has consulted for Otsuka Pharmaceuticals, Neurocrine Biosciences, Jazz, Teva and the Centers of Psychiatric Excellence and Continuous Precision Medicine and received research support from Otsuka Pharmaceuticals and Veterans’ Affairs grant IK2CX001397. K.G. has been on the advisory board of Sunovion and Otsuka Pharmaceuticals and received research funding from AstraZeneca, the Cleveland Foundation and the Brain and Behavioral Research Foundation. K.G. has been a speaker for AstraZeneca, Pfizer and Sunovion. W.Z.P. has been on the advisory board and/or consulted for Takeda, Lilly, Praxis, Astellas, Otsuka and Noven. W.Z.P. has been on the DSMB for Agene-Bio and has stock ownership in Merck.
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Krystal, A.D., Pizzagalli, D.A., Smoski, M. et al. A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia. Nat Med 26, 760–768 (2020). https://doi.org/10.1038/s41591-020-0806-7
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DOI: https://doi.org/10.1038/s41591-020-0806-7
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