217-LB: YH34160, a Novel Long-Acting GDF15 Fusion Protein, Elicits Potent and Sustained Body Weight Loss in Obese Animal Models

Growth differentiation factor 15 (GDF15) is a multifunctional protein associated with energy homeostasis and body weight regulation. GDF15 has emerged as an attractive therapeutic target to treat obesity-related metabolic disorders. GDF15 reduces food intake with unique mode of action via its receptor GDNF family receptor α-like (GFRAL) and the co-receptor RET. YH34160 is an Fc fusion GDF15 variant engineered to have extended half-life and improved binding affinity to GDF15 receptors (GFRAL/RET). YH34160 exhibited superior in vitro efficacy over Fc fusion protein comprising wild-type GDF15 in GFRAL/RET overexpressing cells. Based on rodent and monkey pharmacokinetic (PK) data, YH34160 is expected to have an optimal PK profile for once-weekly dosing in human. In addition, YH34160 exhibited a potent and sustained weight-lowering effect in the obese mice models. After single subcutaneous injection in diet-induced obese (DIO) mice, YH34160-treated groups showed sustained and dose-dependent body weight reduction. Following 8-week repeat dose study in DIO mice, YH34160-treated groups induced more potent and sustained body weight loss compared to the group of long-acting glucagon like peptide-1 receptor agonist (GLP-1RA). Significant body weight reduction and improved lipid profiles by YH34160 was also proved in leptin-deficient (ob/ob) mice compared to GLP-1RA. Furthermore, YH34160 in combination with a GLP-1RA demonstrated a complementary effect on body weight loss compared to that of each single agent treatment. These findings indicate that YH34160 would be a promising therapeutic candidate for the treatment of human obesity.