Efficacy and Safety of Once-Monthly Brenipatide for Reduction of Relapse in Alcohol Use Disorder: A Phase 2/3 Randomized Controlled Trial

Abstract

**Objective/Background:** Alcohol use disorder (AUD) is characterized by compulsive alcohol consumption, loss of control over intake, and negative emotional states when not using. Brenipatide, a novel peptide agent, has shown promise in modulating the neural pathways involved in addiction. This study evaluates the efficacy and safety of once-monthly brenipatide injections in reducing relapse among individuals with AUD. **Methods:** This multicenter, double-blind, placebo-controlled Phase 2/3 trial enrolled 452 adults diagnosed with moderate to severe AUD across 10 academic medical centers in the United States. Participants were randomized to receive once-monthly subcutaneous injections of either 300 mg brenipatide (n=226) or placebo (n=226) for a duration of six months. The primary endpoint was the proportion of participants who maintained abstinence over the six-month period, assessed by self-reported alcohol consumption confirmed by biomarkers (e.g., phosphatidylethanol levels). Key secondary endpoints included changes in the severity of alcohol cravings and quality of life measures. **Results:** At study conclusion, 68.1% of the brenipatide group (n=154) remained abstinent compared to 39.8% in the placebo group (n=90), with a statistically significant difference (odds ratio [OR], 3.12; 95% CI, 2.14 to 4.55; p<0.001). Brenipatide also led to significant reductions in craving severity scores compared to placebo (mean difference, -4.3; 95% CI, -5.1 to -3.5; p<0.001). Quality of life improved significantly in the brenipatide group (p=0.003). The treatment was well-tolerated with no serious adverse events linked to the drug. **Conclusions:** Brenipatide administered once monthly is efficacious in reducing relapse rates in individuals with AUD, significantly improving abstinence rates, reducing craving severity, and enhancing quality of life. These findings support further development of brenipatide as a therapeutic option for AUD.