Introduction and Objective: AT7687 is a novel GIP receptor (GIPR) peptide antagonist being developed for weight management and cardiometabolic disease. Cagrilintide is a dual amylin and calcitonin receptor (CTR) agonist with established weight-lowering efficacy. To assess the therapeutic potential of combining GIPR antagonism with amylin/CTR agonism, a chronic study was conducted in non-human primates (NHPs). Methods: High-fat-fed obese, insulin-resistant NHPs were randomized to placebo, cagrilintide, AT7687, or the combination for 42 days, followed by a 15-day washout whilst fed ad libitum. Assessments included weight, food intake, DXA, ivGTT, and metabolic and safety profiling. Results: AT7687 alone or combined with cagrilintide was well tolerated. At the end of treatment, the cagrilintide and AT7687 groups achieved a vehicle-adjusted 7.0% and 2.7% weight loss, respectively, whilst the combination group achieved 11.4% weight loss (p0.0001 combination vs. vehicle; p=0.039 vs. cagrilintide). Total energy intake was similar between the combination and cagrilintide groups. Only the combination improved fat-to-lean mass ratio. Changes from baseline in glucose disappearance rate during ivGTT were minimal in the monotherapy groups (-1.3% for cagrilintide; 0.9% for AT7687) and improved 18.9% from baseline in the combination group (p=0.011 vs. placebo; p=0.103 vs. cagrilintide), vs. -11.3% decline in the vehicle group. Conclusion: Combining amylin/CTR agonism with GIPR antagonism yields supra-additive benefits on weight, body composition, and insulin sensitivity in obese, insulin-resistant NHPs. The decoupling between weight loss and energy intake suggests effects beyond appetite suppression. These findings support AT7687 as a differentiated, next-generation obesity therapy with additional promising benefits for patients requiring improved glycemic control. Disclosure M. Jensen: None. S. Sanni: None. L. Hartvig: None. A. Baladi Nejad: Employee; Current; Antag Therapeutics. Employee; Ended; Novo Nordisk A/S. M. Tang-Christensen: Stock/Shareholder; Current; Novo Nordisk A/S, Zealand Pharma A/S, Gubra. Advisory Panel; Current; Merck Sharp Ended; Zealand Pharma A/S, Novo Nordisk. A.H. Sparre-Ulrich: None.
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