1103-OR: GUB-UCN2 as Monotherapy and in Combination with Semaglutide Increases Muscle Mass, Reduces Fat Mass, and Improves Metabolic Outcomes in Aged Diet-Induced Obese Rats

Introduction and Objective: Urocortin-2 (UCN2), an endogenous agonist of corticotropin-releasing hormone receptor 2 (CRHR2), plays an important role in regulating muscle mass, energy balance and glucose metabolism. Here, we evaluated GUB-UCN2, a potent long-acting CRHR2-selective UCN2 analogue, as monotherapy and in combination with semaglutide, in aged diet-induced obese (DIO) rats. Methods: 5-week-old DIO rats, pre-fed a high-fat diet for 24 weeks, received (SC, QD) vehicle, GUB-UCN2 (low and medium dose, respectively), semaglutide (10 nmol/kg), or GUB-UCN2 and semaglutide co-treatment for 12 weeks. Other DIO rats were pretreated with semaglutide for 3 weeks before switching to GUB-UCN2 combination therapy for additional 9 weeks. Results: Compared to vehicle, 12 weeks of GUB-UCN2 treatment increased whole-body lean mass by ≈+14% (both doses) and reduced whole-body fat mass by -22% (low dose) and -33% (medium dose), whereas semaglutide reduced both lean (-3%) and fat mass (-20%). When combined with semaglutide, GUB-UCN2 preserved and increased lean mass (~+8%) while amplifying fat mass loss (-48% to -55%) with maintained body weight loss. GUB-UCN2 increased soleus muscle weight (+25-29%), volume (+29%), and cross-sectional area (+21-24%), and reduced intramyocellular lipid content (-41% to -57%). GUB-UCN2, both as monotherapy and in combination with semaglutide, produced more robust improvements in glucose, insulin, leptin, and triglycerides than semaglutide alone. Conclusion: GUB-UCN2 monotherapy increased lean and muscle mass while reducing fat mass in aged DIO rats. In combination with semaglutide, GUB-UCN2 preserved and expanded lean and muscle mass during weight loss, further enhanced fat mass reduction, and improved glycemic control and lipid profiles. These results support GUB-UCN2 as a promising therapeutic candidate to preserve and expand muscle mass and enhance fat loss, alone or in combination with GLP-1 receptor agonist therapies. Disclosure H. Haahr: Employee; Current; Gubra. Stock/Shareholder; Current; Novo Nordisk A/S. T. Porsgaard: None. M. Hahn: Employee; Current; Gubra. A.K. Sárvári: None. C. Hjørringgaard: Employee; Current; Gubra. S.T. Bak: None. H.H. Hansen: Employee; Current; Gubra. L. Thisted: None. L.H. Kruse: None. L. Dalbøge: None.