Preliminary effects of oral ANS-6637, an ALDH2 inhibitor, on cue-induced craving, safety and alcohol consumption among adults with alcohol use disorder: a proof-of-concept, randomized, human laboratory trial.

Aims: We evaluated the safety, efficacy, and patient adherence to oral ANS-6637, a selective, reversible inhibitor of aldehyde dehydrogenase 2 (ALDH2), for treating alcohol use disorder (AUD).

Methods: A 3-arm, double-blind, randomized, proof-of-concept human laboratory study embedded in a 5-week multisite clinical trial tested 200 mg and 600 mg daily doses of ANS-6637 compared to placebo in treatment-seeking adults with AUD. After 1 week of medication, participants completed an alcohol cue reactivity session. Drinking and safety assessments were measured during treatment; other exploratory outcomes were measured 1 week after treatment ended.

Results: The study was terminated following enrollment of 43 of 81 planned participants due to clinically significant, reversible increases in liver enzymes in three women. Adverse events consistent with ALDH2 inhibition in the presence of alcohol (heart rate/palpitations, flushing, nausea) were dose dependent. Group differences in cue-elicited craving were not significant; effect sizes (Cohen's d) comparing the 200 mg and 600 mg doses to placebo were .71 and .06, respectively. Secondary endpoints did not differ significantly between groups; Cohen's d ranged from .31 to .57 for the 600 mg dose compared to placebo for continuous drinking outcomes.

Conclusions: Findings of liver toxicity with ANS-6637 led to early termination and reduced power to test hypotheses. Effect size estimates are consistent with the hypothesis that selective ALDH2 inhibition may reduce craving and drinking, however these estimates may be unreliable due to the small sample size. Additional research with non-hepatotoxic selective and reversible ALDH2 inhibitors is needed to evaluate this approach to AUD pharmacotherapy.