299-OR: Discovery of Long-Acting Unimolecular Peptide Tetra-agonists Targeting GLP-1, GIP, Amylin, and Calcitonin Receptors for Enhanced Metabolic Benefits in Animal Models of Obesity

Objective: The burgeoning prevalence of obesity and associated co-morbidities necessitates innovative approaches for safe and efficacious therapies. We describe the characterization of PTT-A, a novel long-acting peptide agonist for GLP-1, GIP, Amylin and Calcitonin Receptors, in rodent models and assessed its efficacy against the dual GIPR/GLP-1R agonist Tirzepatide. Methods: In vitro assays used recombinant cell lines expressing individual receptors to assess GLP-1, GIP, Amylin and Calcitonin receptor agonism. Multiple metabolic endpoints were examined in rodents, including acute food intake and calcium regulation effects of PTT-A in lean rats, acute glucose-lowering effects in lean mice, and its chronic effects in diet-induced obesity (DIO) rats compared to Tirzepatide. Results: PTT-A exhibited potent GIP, GIP, Amylin, and Calcitonin receptor agonism in cAMP assays, and induced decreases in blood glucose and calcium levels in acute studies in lean rodents. In lean rats, PTT-A dose-dependently reduced cumulative food intake. Chronic studies in DIO rats revealed significant reduction in cumulative food intake and body weight, driven by decreases in fat mass without loss of muscle mass, unlike that seen with Tirzepatide. PTT-A demonstrated robust efficacy for glucose and plasma lipid lowering, insulin sensitization and liver benefits, as indicated by lowered plasma insulin, alanine aminotransferase and liver triglycerides, while outperforming Tirzepatide at equivalent doses. Conclusion: PTT-A is a novel tetra-receptor agonist, offering superior outcomes for weight loss, glycemic control, insulin sensitization, and liver health compared to Tirzepatide. These findings underscore the promise of such poly-pharmacological agents to tackle the complex challenges associated with obesity-related metabolic disorders.