85-OR: A Novel Unimolecular Peptide Tetra-agonist (PTT-A) Targeting GLP-1, GIP, Amylin, and Calcitonin Receptors with Superior Weight Loss Effects vs. Tirzepatide While Preserving Muscle in DIO Rats

Abstract

Introduction and Objective: The prevalence of obesity and associated disorders necessitates innovative approaches for safe and efficacious therapies. This study aims to characterize PTT-A, a novel unimolecular tetra-agonist in DIO rats and assess its efficacy against Tirzepatide. Methods: DIO rats were dosed for 3 weeks with PTT-A and Tirzepatide and multiple endpoints were examined, including body weight (BW), food intake (FI), body composition by carcass analysis and MRI, metabolic parameters and liver health. Results: Treatment with PTT-A at 10 and 30 nmol/kg over 21 days resulted in significant reductions in cumulative FI and BW (14.3±1.52% and 19.2±0.89% vs vehicle, respectively) driven by reductions in fat mass with no loss of muscle mass. Tirzepatide at 30 nmol/kg reduced BW only by 12.1±0.81% vs vehicle with a decrease in both fat and muscle mass. Gastrocnemius and soleus muscle weights were reduced by approximately 26% with Tirzepatide, with no reduction in muscle weight with PTT-A at same dose. Additionally, PTT-A exhibited robust efficacy in triglycerides lowering, insulin sensitization and liver health, as evidenced by reductions in plasma aminotransferase, plasma lipids, hepatic triglycerides, and liver histology, that surpassed Tirzepatide’s effects at equivalent doses. Conclusion: PTT-A represents a promising novel tetra-agonist that demonstrated enhanced efficacy in weight loss, insulin sensitization, lowering lipids and liver health relative to Tirzepatide. The profound BW reduction after 3 weeks treatment was through fat loss while preserving the muscle. These findings show the potential of tetra-agonists as multifaceted therapeutic options for addressing the challenges of obesity-related metabolic disorders. Disclosure: S. Ghosh: Consultant; Pep2Tango Therapeutics, Abvance Therapeutics. P. Valdecantos: Research Support; Pep2Tango Therapeutics. P. Rada: Research Support; Pep2Tango Therapeutics. A.M. Valverde: Research Support; Pep2Tango Therapeutics. C.M. Rondinone: Employee; Pep2Tango Therapeutics.