# Histamine H3 Receptor as a target for alcohol use disorder: challenging the predictability of animal models for clinical translation in drug development

## TL;DR

This paper discusses the development and clinical testing of BP1.3656B, a drug targeting the histamine H3 receptor for alcohol use disorder, highlighting the challenges in translating preclinical results to human trials.

## Contribution

The study introduces BP1.3656B as a novel histamine H3 receptor antagonist and evaluates its clinical translation challenges in treating AUD.

## Key findings

- BP1.3656B showed high brain occupancy and good pharmacokinetics in humans.
- The drug had no effect on alcohol self-administration in non-treatment seekers or on heavy drinking days in treatment-seekers.
- The results emphasize the importance of Phase IIa human laboratory studies for de-risking drug targets for AUD.

## 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.