Topline results were announced from a phase 3 trial evaluating the efficacy and safety of AD04 (ondansetron) in patients with alcohol use disorder (AUD) and selected polymorphisms in the serotonin transporter and receptor genes.

AD04 is a genetically targeted, serotonin-3 receptor antagonist that is believed to reduce alcohol intake by interfering with the dopamine reward system. The multicenter, randomized, double-blind, placebo-controlled ONWARD trial (ClinicalTrials.gov Identifier: NCT04101227) included 302 adults with AUD and selected polymorphisms in the serotonin transporter and receptor genes.

Prior to enrollment, patients were genetically screened and stratified by the severity of drinking into heavy drinkers (averaging less than 10 drinks per day) or very heavy drinkers (averaging at least 10 drinks per day). 

Patients were randomly assigned to receive either AD04 or placebo orally twice daily for 24 weeks in conjunction with brief psychological counseling. The primary endpoint was the change from baseline in the monthly number of (heavy) drinking days (HDD) during the last 8 weeks (weeks 16 to 24).

For heavy drinkers, treatment with AD04 demonstrated a statistically significant reduction in heavy drinking days at month 6 from baseline compared with placebo (P =.03), with a similar trend observed in the combined month 5 and 6 analysis (P =.07). In month 6, heavy drinkers treated with AD04 had a mean reduction of approximately 79% in heavy drinking compared with baseline.

For both heavy and very heavy drinkers, treatment with AD04 showed a nonstatistically significant trend in the reduction in heavy drinking days at month 6 from baseline, which was influenced by the high placebo response among very heavy drinkers. There was a similar nonstatistically significant trend observed in the combined month 5 and 6 analysis.

Compared with patients in the placebo group, heavy drinkers treated with AD04 had an overall significant difference in the severity of their AUD diagnosis (P =.04), under the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), with an 84% decrease in the number of heavy drinking patients meeting the criteria for AUD diagnosis.

The safety profile of AD04 was similar to placebo. The most common adverse events in either treatment arm were headache, insomnia, decreased blood magnesium, and fatigue; all of these were reported as mild to moderate in severity.

“Among heavy drinkers, which make up the majority of my practice, we saw a clear and statistically significant reduction in heavy drinking days for those patients receiving AD04 vs placebo,” said Professor Hannu E.R. Alho, Emeritus Professor of Addiction Medicine at the University of Helsinki and Principal Investigator for the ONWARD trial. “These results demonstrate the effectiveness of AD04 for heavy drinker AUD patients.”

Reference

Adial Pharmaceuticals announces topline results for Onward™ phase 3 trial for AD04 in patients with alcohol use disorder. News release. Adial Pharmaceuticals, Inc. Accessed July 20, 2022. https://www.globenewswire.com/news-release/2022/07/20/2482531/26135/en/Adial-Pharmaceuticals-Announces-Topline-Results-For-Onward-Phase-3-Trial-for-AD04-in-Patients-with-Alcohol-Use-Disorder.html