MON-LB020 Compound H Causes a Sustained Reduction in Food Intake and Body Weight in Obese Cynomolgus

Obesity is associated with increased risk of diabetes and cardiovascular disease. Evidence is accumulating that significant WL (>10%) may reduce this risk. GDF15 is a secreted circulating polypeptide associated with energy balance. The receptor for GDF15, Gfral, is expressed in the area postrema and mediates the inhibitory effects of GDF15 on food intake. Compound H (CpdH) is a GDF15 agonist on a half-life extension platform, suitable for once-weekly dosing. We sought to test the durability of the food intake suppression and body weight loss with once weekly dosing of CpdH in the spontaneously obese cynomolgus non-human primate (NHP) model. As a translational control we included dulaglutide (dula), a long-acting GLP-1 agonist, to enable efficacy modeling and validation of the animal model. PK/PD simulations derived from single-dose lean and obese NHP studies were used for dose selection; CpdH or dula was administered SC once weekly in a biologic naïve spontaneously obese cynomolgus (population BMI 46.0±1.0Kg/m2 with 15.1±1.5% total body fat (n=32) at baseline). Chronic treatment of animals with CpdH at 1 and 10nmol/kg once weekly reduced food intake in a dose related manner relative to vehicle. A commensurate, sustained reduction in body weight (up to 16.2±4.9%) was observed at steady state exposures. The injection of dulaglutide control caused rapid, transient reduction in food intake and a 3.8% reduction in vehicle corrected body weight over 12 weeks. A dose-response relationship for CpdH was formally demonstrated. In conclusion, CpdH is a novel agent for the treatment of human obesity and type 2 diabetes. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.