Treatment for cannabis use disorder

Abstract Our goal is to develop an innovative pharmacotherapy for cannabis use disorder (CUD) that affects over 4 million Americans. We propose to develop a novel second generation PARTIAL inverse agonist of the cannabinoid 1 receptor (CB1) that has a benign behavioral profile for CUD. Cannabinoids are the second most abused class of drug in the world and there is no FDA approved medication for CUD -- making this an area of urgent need. The psychoactive effects of cannabis and synthetic cannabinoids result from activation of central CB1 receptors. Blocking the rewarding and craving properties of drugs of abuse is a well-validated and accepted strategy for substance use disorders (SUD) without a strong adverse physical withdrawal component. Rimonabant is a potent FULL inverse agonist of the CB1 receptor that was approved in Europe as an anti-obesity agent. Unfortunately, rimonabant produced adverse dysphoric effects in ~6% of users -- effects likely due to sustained high brain exposure and potent inverse agonism, which led to its eventual discontinuation. In human studies, rimonabant was efficacious in treating many aspects of CUD. Artiam Bio is developing the next generation of CB1 antagonists that are expected to have a superior adverse effect profile compared to rimonabant and previous clinical candidates. Artiam Bio’s lead compound is an orally active, potent, and selective CB1 partial inverse agonist with limited brain penetration. This compound is functionally as efficacious as rimonabant but produces no dysphoria/anhedonia in rodent studies. Further development of this compound is proposed through three aims. Through aim 1, ~500 g of the compound will be synthesized using an established chemical route leveraging upon Artiam’s experience with a congener. Through aims 2 and 3, dose range finding toxicological studies will be performed in two species and toxicokinetic parameters will be established. Successful completion of this phase 1 SBIR application will pave the way for GLP regulatory studies and other IND-enabling activities of Artiam’s lead candidate for CUD.