# A Novel ALDH2 Inhibitor for the Treatment of Alcohol Use Disorder: Preclinical Findings

## TL;DR

A new long-acting injectable ALDH2 inhibitor, SOPH-110S, shows promise in preclinical studies for treating alcohol use disorder with high potency and safety.

## Contribution

SOPH-110S is a novel ALDH2 inhibitor with long-acting injectable formulation and superior safety compared to existing treatments like disulfiram.

## Key findings

- SOPH-110S demonstrated high potency and no off-target effects in a panel of 84 common targets.
- It showed positive proof-of-mechanism data in rats and no CYP interactions or hERG channel inhibition.
- The compound is a potent, dose-dependent ALDH2 inhibitor comparable to DETC-MeSO with no cardiovascular safety concerns.

## Abstract

What are the main findings?
SOPH-110S is a novel ALDH2 inhibitor intended to be developed as a long-acting injectable for the treatment of alcohol use disorderPreclinical studies that supported an approved IND in the US demonstrated high potency, acceptable safety, no off-target effects in a panel of 84 common targets, no CYP interactions, and positive proof-of-mechanism data in rats.

SOPH-110S is a novel ALDH2 inhibitor intended to be developed as a long-acting injectable for the treatment of alcohol use disorder

Preclinical studies that supported an approved IND in the US demonstrated high potency, acceptable safety, no off-target effects in a panel of 84 common targets, no CYP interactions, and positive proof-of-mechanism data in rats.

What are the implications of the main findings?
SOPH-110S has preclinical promise supporting clinical evaluation.SOPH-110S data, to date, support its potential as a safer, better-tolerated, long-acting injectable therapy for AUD that is superior to oral disulfiram.

SOPH-110S has preclinical promise supporting clinical evaluation.

SOPH-110S data, to date, support its potential as a safer, better-tolerated, long-acting injectable therapy for AUD that is superior to oral disulfiram.

Background: Alcohol use disorder is a common condition with high morbidity and mortality and no highly effective treatments. Achieving and maintaining abstinence is necessary or desired for many persons with AUD, but is difficult due to the nature of the condition. Pharmacologic inhibition of the enzyme ALDH2, which increases levels of the substrate acetaldehyde when alcohol is imbibed, can serve as a powerful enforcer of efforts to remain abstinent. Disulfiram is an approved ALDH2 inhibitor via its active metabolite DETC-MeSO, but has many limitations, including numerous adverse effects, hepatotoxicity, oral administration, and unpredictable mechanistic activity. Methods: SOPH-110S, an analog of DETC-MeSO, was evaluated in a series of experiments to assess mechanism, pharmacokinetics in male beagle dogs, cardiovascular safety in telemeterized male beagle dogs, selectivity, off-target activity, CYP inhibition, and proof of mechanism in a rat model that included dosing and alcohol challenge followed by analysis of liver ALDH2 inhibition. Results: SOPH-110S showed high potency with a comparable IC50 vs. positive controls and no physiologically relevant off-target binding in an 84-target panel. It did not inhibit or induce any major CYP enzymes or meaningfully inhibit the hERG channel. After 10 days’ dosing in rats, followed by administration of alcohol, SOPH-110S was a highly potent, dose-dependent inhibitor of ALDH2, comparable to DETC-MeSO. No cardiovascular safety concerns were found at multiples above expected clinical doses. Conclusions: The preclinical data support further clinical study of SOPH-110S as a potential ALDH2 inhibitor treatment for AUD. The FDA approved the IND to conduct a first-in-man phase 1 study in September 2025.