3083-LB: Petrelintide, a Human Amylin Analog for the Treatment of Obesity: Efficacy and Safety from the Phase 2 Trial, ZUPREME 1

Introduction and Objective: Petrelintide is being developed for long-term obesity pharmacotherapy, leveraging a mechanism of action (MOA) distinct from existing treatments to potentially improve tolerability and support sustained use. This trial compared the efficacy, safety, and tolerability of petrelintide vs placebo, as an adjunct to lifestyle changes, in people with obesity or overweight with complications. Methods: In this double-blind, parallel-group, dose-finding trial, adults were randomized (5:1) to weekly s.c. injections of five doses of petrelintide or placebo. Doses were escalated for up to 16 weeks (in 4-week steps) to the assigned maintenance dose, which continued through Week 42. Available safety follow-up data are reported. Results: In total, 485 adults were randomized and dosed (53% female; mean age: 47 years, BMI: 36.7 kg/m2; body weight: 107.1 kg). Petrelintide led to mean reductions in body weight from baseline to Week 42 of up to 10.7% vs 1.7% for placebo (efficacy estimand; p0.001). The target dose was reached by 88-98% of participants on petrelintide. Most (75%) gastrointestinal (GI) AEs were mild. Nausea was the most common GI AE, reported for 19.6% of participants on petrelintide vs 6.2% on placebo. Vomiting was rare with petrelintide (3.0% vs 6.2% for placebo), while the rates of diarrhea and constipation were similarly low (7.5%) for petrelintide and placebo. Only 1.5% of participants discontinued petrelintide due to GI AEs, and there were no unexpected safety findings. Petrelintide was associated with meaningful improvements in key cardiovascular risk factors (hs-CRP, lipids, BP and waist circumference). Conclusion: In a gender-balanced population, petrelintide achieved clinically meaningful weight reduction at 42 weeks in this phase 2 trial, with a GI tolerability profile that was largely similar to placebo. Petrelintide has the potential to be an effective and very well-tolerated treatment for sustained long-term obesity therapy, via a distinct MOA compared to current therapies. Disclosure W. Garvey: Advisory Panel; Current; Boehringer Ingelheim International GmbH, Eli Lilly and Company. Research Support; Current; Eli Lilly and Company. Advisory Panel; Current; Novo Nordisk. Research Support; Current; Novo Nordisk. Advisory Panel; Ended; Pfizer Inc. Advisory Panel; Current; Fractyl Health, Inc., Zealand Pharma A/S. Research Support; Current; Zealand Pharma A/S. Advisory Panel; Current; Genentech, Inc. Research Support; Current; Genentech, Inc. Advisory Panel; Current; TERNS Pharmaceuticals. Research Support; Current; TERNS Pharmaceuticals. Advisory Panel; Current; Neurocrine Biosciences, Inc. Advisory Panel; Ended; Keros Therapeutics. Advisory Panel; Current; Gan Ended; Corcept Therapeutics. Advisory Panel; Current; Metsera, Graviton, AbbVie Inc., Regeneron Pharmaceuticals Inc., Madrigal Pharmaceuticals, Inc. Research Support; Current; Viking Therapeutics, Kaleira. L. Connery: Advisory Panel; Current; Boehringer Ingelheim International GmbH. Research Support; Current; Boehringer Ingelheim International GmbH. Advisory Panel; Current; Eli Lilly and Company. Research Support; Current; Eli Lilly and Company, Merck Current; Zealand Pharma A/S. Employee; Ended; MC2 Therapeutics. B.F. Hagen: Employee; Current; Zealand Pharma A/S. Stock/Shareholder; Current; Zealand Pharma A/S. L. Larsen: Employee; Current; Zealand Pharma A/S. D. Hesse: Employee; Current; Zealand Pharma A/S. Funding Zealand Pharma A/S