1321-OR: Superior Quality of Weight Loss with a Novel Unimolecular Tetra-Agonist Peptide Targeting GLP-1, GIP, Amylin, and Calcitonin Receptors vs. Tirzepatide and Cagrisema in Diet-Induced Obese Rats

Introduction and Objective: The rising prevalence of obesity and related comorbidities highlights the need for safe, effective, and durable therapies. We evaluated PTT-A, a novel long-acting tetra-agonist targeting GLP-1, GIP, amylin, and calcitonin receptors, in diet-induced obese (DIO) rats and compared its efficacy with tirzepatide and CagriSema. Methods: DIO rats received PTT-A (10 or 30 nmol/kg), tirzepatide (30 nmol/kg), or CagriSema (2 nmol/kg cagrilintide plus 2 nmol/kg semaglutide) for 21 days. Endpoints included body weight, food intake, body composition assessed by carcass analysis, DEXA, and MRI, and metabolic parameters. Results: PTT-A produced dose-dependent reductions in cumulative food intake and body weight (−12% and −19% vs vehicle at 10 and 30 nmol/kg, respectively), driven by marked fat mass loss with preservation of lean mass. Tirzepatide and CagriSema each reduced body weight by approximately 12% versus vehicle. PTT-A reduced inguinal and epididymal fat by 36% and 50%, compared with 25% reductions with tirzepatide or CagriSema. DEXA confirmed greater total fat mass reduction with high-dose PTT-A (84 g) versus tirzepatide or CagriSema (60 g). Carcass analysis and MRI demonstrated significant skeletal muscle loss with tirzepatide and CagriSema, whereas PTT-A preserved muscle mass. PTT-A also showed superior improvements in metabolic parameters, including reductions in glucose, insulin, and triglycerides. Conclusion: PTT-A demonstrates superior weight loss efficacy and quality, characterized by preferential fat loss and muscle preservation, compared with tirzepatide and CagriSema. These findings support tetra-agonism as a promising therapeutic strategy for obesity and associated metabolic disorders and may offer durable clinical benefits with favorable safety profiles overall. Disclosure S.S. Ghosh: Consultant; Current; Pep2Tango Therapeutics LLC. Stock/Shareholder; Current; Pep2Tango Therapeutics LLC. Consultant; Current; Epirium Bio, Flagship Pioneering. B. Herrero: Research Support; Current; Pep2Tango Therapeutics. M. Valdecantos: Research Support; Current; Pep2Tango Therapeutics. P. Rada: Research Support; Current; Pep2Tango Therapeutics. A.M. Valverde: Research Support; Current; Pep2Tango Therapeutics. C. Rondinone: Employee; Current; Pep2Tango Therapeutics Inc. Stock/Shareholder; Current; Pep2Tango Therapeutics Inc.