Abstract
There is an important need to advance medication development for alcohol use disorder (AUD). BP1.3656B, a highly potent and selective histamine H3 receptor inverse agonist/antagonist, has been developed. Preclinical studies revealed high affinity, good pharmacokinetic profile, good brain penetration, and favorable safety. BP1.3656B reduced alcohol drinking and alcohol-seeking behavior in rodents. Phase I studies revealed good tolerability/pharmacokinetic in humans. Positron emission tomography revealed high brain occupancy in humans. Based on this favorable profile, two trials were conducted in subjects with AUD. In non-treatment seekers, BP1.3656B had no impact on intravenous alcohol self-administration (IV-ASA). A randomized clinical trial testing three doses of BP1.3656B versus placebo in treatment-seekers with AUD showed no reduction of heavy drinking days. Collective results illustrate the challenges inherent to clinical translation of AUD therapies, and reinforce the use of Phase IIa human laboratory paradigms as an important tool to de-risk translation of innovative drug targets for AUD.
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The data that support the findings of this study are not publicly available but may be obtained from the corresponding author upon reasonable request.
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Acknowledgements
Research reported in this publication was supported in part by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number R21AA026035 (IV-ASA study). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Vijay Ramchandani at the National Institutes of Alcohol Abuse and Alcoholism (NIAAA) and Martin Plawecki and Sean O’Connor at the Indiana Alcohol Research Center (NIH P60 AA007611) for their consultation and support. The authors thank Isabelle Nagmar and Sabine Rouanet for their experimental contribution to in vitro assays.
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BLF, MN, JJ, CH and JCS contributed to the conceptualization of the studies reported in this manuscript. TC, SK, IBB, MU, DP, XL, IB, PMR, MC, PR, OF, and JML contributed to development and design of methodologies. MN, JJ, PMR, and XL supported data synthesis and formal analyses. PDC, PS, JC, SK, IBB, MU, DP, and MC contributed to the investigation of the studies. BLF, JJ, MN and PS contributed to the writing of this manuscript. All authors critically reviewed content and approved the final version for publication.
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This work was supported by Bioprojet. Two authors, Jeanne-Marie Lecomte and Jean-Charles Schwartz are shareholders of Bioprojet. Thierry Calmels, Stéphane Krief, Isabelle Berrebi-Bertrand, Marilyne Uguen, David Perrin, Xavier Ligneau, Marc Capet, Philippe Robert, and Olivier Finance are employees of Bioprojet. Dr. Bernard Le Foll has received travel support to attend an event by Bioprojet. He is supported by CAMH, Waypoint Centre for Mental Health Care, a clinician-scientist award from the department of Family and Community Medicine of the University of Toronto and a Chair in Addiction Psychiatry from the department of Psychiatry of University of Toronto.
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Le Foll, B., Naassila, M., Jeanblanc, J. et al. Histamine H3 Receptor as a target for alcohol use disorder: challenging the predictability of animal models for clinical translation in drug development. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03807-y
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DOI: https://doi.org/10.1038/s41398-026-03807-y
