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Lessons learned from using fMRI in the early clinical development of a mu-opioid receptor antagonist for disorders of compulsive consumption

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Abstract

Functional magnetic resonance imaging (fMRI) has been widely used to gain a greater understanding of brain circuitry abnormalities in CNS disorders. fMRI has also been used to examine pharmacological modulation of brain circuity and is increasingly being used in early clinical drug development as functional pharmacodynamic index of target engagement, and to provide early indication of clinical efficacy. In this short review, we summarize data from experimental medicine and early clinical development studies of a mu-opioid receptor antagonist, GSK1521498 developed for disorders of compulsive consumption including binge eating in obesity. We demonstrate how fMRI can be used to answer important questions of early clinical drug development relating to; (1) target engagement, (2) dose response relationships, (3) differential efficacy and (4) prediction of behavioural and clinically relevant outcomes. We also highlight important methodological factors that need to be considered when conducting fMRI studies in drug development given the challenges faced with small sample sizes in Phase 1 and early proof of mechanism studies. While these data highlight the value of fMRI as a biomarker in drug development, its use for making Go/No-go decisions is still faced with challenges given the variability of responses, interpretation of brain activation changes and the limited data linking drug induced changes in brain activity to clinical or behavioural outcome. These challenges need to be addressed to fulfil the promise of fMRI as a tool in clinical drug development.

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Acknowledgements

All the work discussed in this paper was conducted at Glaxo Smith Kline. Authors would like to acknowledge the significant contribution of Prof. Ed Bullmore who led the clinical development of GSK1521498 with Prof Pradeep Nathan.

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Authors and Affiliations

  1. Experimental Medicine (Neuroscience), Sosei Heptares, Cambridge, UK

    Pradeep J. Nathan & Geor Bakker

  2. Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge, UK

    Pradeep J. Nathan

  3. The Monash School of Psychological Sciences, Monash University, Melbourne, Australia

    Pradeep J. Nathan

  4. Department of Psychiatry and Psychology, Maastricht University, Maastricht, Netherlands

    Geor Bakker

  5. Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Geor Bakker

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  1. Pradeep J. Nathan
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Correspondence to Geor Bakker.

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This article belongs to a Special Issue on Imaging for CNS drug development and biomarkers

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Nathan, P.J., Bakker, G. Lessons learned from using fMRI in the early clinical development of a mu-opioid receptor antagonist for disorders of compulsive consumption. Psychopharmacology 238, 1255–1263 (2021). https://doi.org/10.1007/s00213-019-05427-5

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