A Phase I randomized clinical trial testing the safety, tolerability and preliminary pharmacokinetics of the mGluR5 negative allosteric modulator GET 73 following single and repeated doses in healthy volunteers

Abstract Preclinical work suggests that the metabotropic glutamate receptor subtype 5 (mGlu5) may represent a novel target to treat neuropsychiatric disorders, including alcohol use disorder and obesity. The goal of this first-in-man study was to evaluate the safety, tolerability and pharmacokinetics (PK) of GET 73 (PubChem SID: 329974174), a novel mGluR5 negative allosteric modulator. This was a double-blind, placebo-controlled, ascending dose, Phase I study conducted in healthy male volunteers in two experiments. GET 73 was administered as single ascending doses ( N  = 48; Experiment 1 ; 10, 30, 100, 300, 450, 600-mg) or multiple ascending doses ( N  = 32; Experiment 2 ; 100, 300, 450, 450-mg twice a day). Primary endpoints were the incidence of adverse events (AEs) among drug conditions and drug tolerability. The secondary endpoints were the PK parameters of GET 73 and its metabolite MET 2. Single GET 73 doses of up to 600-mg and repeated ascending doses of up to 450-mg twice/day were safe and well-tolerated. There were no serious or severe AEs. All AEs were mild or moderate in severity. Total GET 73 exposure increased with each increased GET 73 dose. A dose-related increase in mean maximum plasma drug concentration was observed after repeated dosing. Maximum plasma drug concentrations occurred between 0.5 and 2.05 h after administration in all groups for both single and repeated doses. This first-in-human study indicates that GET 73, as single or multiple ascending doses, is safe and well-tolerated when administered to healthy male volunteers.