Histamine H3 Receptor as a target for alcohol use disorder: challenging the predictability of animal models for clinical translation in drug development
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.
Authors
- Philippe Auguste Robert (ORCID: https://orcid.org/0000-0003-1345-5015)
- Olivier Finance
- Jesus Chavarria (ORCID: https://orcid.org/0000-0001-5864-2899)
- Xavier Ligneau (ORCID: https://orcid.org/0000-0003-3097-4482)
- Stéphane Krief (ORCID: https://orcid.org/0000-0002-5543-731X)
- Pablo Rusjan (ORCID: https://orcid.org/0000-0003-0075-2918)
- Marilyne Uguen
- Thierry Calmels
- Patricia Di Ciano (ORCID: https://orcid.org/0000-0001-8509-295X)
- Jérôme Jeanblanc (ORCID: https://orcid.org/0000-0003-0353-2777)
- Mickaël Naassïla (ORCID: https://orcid.org/0000-0002-9788-0918)
- Isabelle Boileau
- Isabelle Berrebi-Bertrand
- Jean Charles Schwartz
- David Perrin
- Christian S. Hendershot
- Pamela Sabioni
- Bernard Le Foll
- Marc Capet
- Jeanne-Marie Lecomte
Institutions
- University of Southern California (US)
- Western University (CA)
- Centre for Addiction and Mental Health (CA)
- Inserm (FR)
- University of Toronto (CA)
- Douglas Mental Health University Institute (CA)
- Mental Health Research Canada (CA)
- Groupe de Recherche sur l'Alcool et les Pharmacodépendances (FR)
- Public Health Ontario (CA)
- Bioprojet (France) (FR)
Publication Details
- Journal
- Translational Psychiatry
- Published
- 2026-01-29
- DOI
- https://doi.org/10.1038/s41398-026-03807-y
- Primary Topic
- Mast cells and histamine
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism