Development of a Drug Candidate for the Treatment of Agitation in Alzheimer's Disease

PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease currently affecting approximately 6.2 million Americans. AD irreversibly damages the central nervous system, thereby inducing a variety of cognitive, behavioral, and psychiatric disturbances that include agitation and aggression. AD aggression occurs in approximately a third of AD patients and meaningfully reduces patient and caregiver quality of life. Currently available pharmacological treatments for AD aggression center on the use of atypical antipsychotic drugs, which have modest efficacy only after chronic administration, and are associated with sedation as well as adverse events including increased rates of upper respiratory tract infections, cardiovascular events, falls, and mortality. Given the modest efficacy and poor safety profile of these treatments, identification of novel treatments for AD aggression with improved efficacy and safety is an important unmet need. The long-term goal of this project is to bring to market a new treatment for AD aggression to improve the quality of life for people with AD and their caregivers. We have discovered a lead drug candidate, PGI-5128, that has a novel mechanism of action to produce serenic-like effects in rodent models of aggression. Phase I of this project seeks to evaluate the efficacy of PGI-5128 in reducing aggressive behaviors in male and female transgenic AD (APP/PS1) mice. Phase II seeks to initiate Investigational New Drug (IND)-enabling non-clinical safety and toxicology studies in rats and dogs conducted according to good laboratory procedures (GLP). Specifically, studies will include 28-day repeat dose toxicology studies with 14-day recovery periods in rat and dog, genotoxicology studies including in vitro bacterial reverse mutation and in vitro and in vivo micronucleus tests, and safety pharmacology studies including in vitro manual patch clamp-based measures at the human ether-à-go-go (hERG) channel, CNS and behavioral and safety pharmacology studies in rats, a respiratory safety study in rats, and a cardiovascular safety study in dogs. Completing these studies will position PGI-5128 for an IND application to allow evaluation in human subjects.