ABSTRACT
In response to RFA-AA-20-007, which calls for the development of medications to treat Alcohol Use Disorders
(AUD), this U01 application proposes research to advance the CB1 neutral antagonist AM6527 towards IND-
enabling studies for treating AUD. The current therapies for AUD are either behavioral or is limited to drugs
such as disulfiram, acamprosate and naltrexone, which are restricted to specific patient populations in terms of
their therapeutic effects. Given these epidemiological, and economic issues related with AUD, there is an
urgent need for novel pharmacological interventions that are more acceptable and selective towards treating
AUD. Rimonabant, a CB1 antagonist, has proven to have unacceptable adverse effects, possibly resulting
from its CB1 inverse agonist actions. In contrast, AM6527 is a novel, selective, CB1 cannabinoid-receptor
neutral antagonist that is devoid of inverse agonist activity. The preclinical pharmacology of AM6527 in rodents
and other prototypes within this class of compounds in nonhuman primates strongly supports their potential
utility as therapy for AUD. AM6527 has a favorable safety profile, without evidence of adverse side effects
(e.g., nausea, depression) that have been reported with CB1-receptor inverse agonists such as rimonabant
and taranabant in preclinical and clinical studies. Based upon these positive preclinical data indicating its
effectiveness as a CB1 antagonist, we plan to move AM6527 toward IND-enabling studies in preparation for
first-in-man studies to treat AUD. Specifically, our work in this U01 proposal is designed to meet the following
aims: Chemistry, manufacturing, and controls of drug substance, non-GLP preclinical safety studies including
hERG, genotoxicity, ADME and dose escalation studies in two species. The subsequent steps will comprise:
Chemistry, manufacturing, and controls of drug product including formulation development, cGMP scale-up,
stability, and analytical methods; toxicokinetics with single and repeat 28-day dosing safety pharmacology,
followed by advisement on product development planning, IND preparation and preclinical regulatory strategy.