THERAPY FOR ALCOHOL USE DISORDER

摘要

Abstract Alcohol use disorder (AUD) is a major global health issue. In the US, AUD affects over 14 million people over the age of 18. While there are three approved drugs for AUD, less than 4% of patients eligible for pharmacotherapy are prescribed a medication – likely due to limited efficacy of currently approved agents. Also, the relapse rate for AUD continues to be exceedingly high. Thus, new therapies are urgently needed for AUD. Both preclinical and clinical evidence suggest that antagonism of the type 1 cannabinoid (CB1) receptor is a promising strategy for AUD. However, first generation CB1 blockers produced adverse psychiatric effects in ~6% of patients making them unsuitable for chronic use. Artiam Bio is developing second generation CB1 blockers that are designed to be efficacious without producing adverse psychiatric effects. Artiam Bio’s approach takes into consideration that intrinsic activity of the CB1 receptor is required for emotional welfare, and that first-generation full inverse agonists/antagonists like SR141716A (rimonabant) completely abrogated this necessary beneficial process. The compounds developed by Artiam, including its lead molecule and backup, are high affinity but low intrinsic efficacy partial inverse agonists that preserve basal activity of the CB1 receptor – thereby reducing the potential of adverse neuropsychiatric events. Supportive evidence comes from rodent studies presented in this application. For this Phase 1 STTR application, Artiam’s team will partner with investigators from University of North Carolina’s Bowles Alcohol Research Center to perform efficacy studies with its lead compound in a rat model of alcohol consumption and relapse. Further, additional behavioral studies are proposed in anxiety-prone mice using a chronic dosing regimen to further de-risk Artiam’s lead compound for clinical development. Successful completion of these studies will pose Artiam’s lead compound, which has good drug-like properties, for clinical development to treat AUD.