Petrelintide, a human amylin analogue for the treatment of obesity (ZUPREME 1): a randomised, double-blind, placebo-controlled, phase 2 trial

Background Petrelintide is a novel, long-acting amylin analogue being developed for long-term treatment of obesity, leveraging a mechanism of action distinct from incretin-based treatments. This phase 2 trial aimed to evaluate the efficacy and safety of once-weekly petrelintide versus placebo in people with obesity. Methods This multicentre, randomised, double-blind, placebo-controlled trial involved 32 sites (public hospitals and private clinics) in Poland, Romania, and the USA. Adults aged at least 18 years without type 2 diabetes, with a BMI of at least 30 kg/m 2 or with a BMI of at least 27 kg/m 2 with hypertension or dyslipidaemia, or both, were randomly assigned (5:1) to self-administered subcutaneous injections of once-weekly maintenance doses of petrelintide (1·0-9·0 mg) or placebo for 42 weeks including dose escalation. Randomisation was done via a central interactive response technology system and was stratified by MRI participation. Participants, trial staff, and the study funder were masked to treatment assignment but not to different maintenance doses; masking was maintained by use of identical vials for petrelintide and placebo. The primary endpoint was percentage change in bodyweight from baseline after 28 weeks. Analyses included all randomly assigned participants who received at least one dose. Missing data were assumed to be missing at random. The trial is registered with ClinicalTrials.gov (NCT06662539) and the Clinical Trials Information System (2024-512549-18) and was completed on Mar 7, 2026. Findings From Dec 9, 2024, to Feb 25, 2025, we screened 714 participants, of whom 493 were randomly assigned and 485 received at least one dose of petrelintide or placebo. 79 participants received at least one dose of treatment with petrelintide 1·0 mg, 81 with petrelintide 2·5 mg, 83 with petrelintide 5·0 mg, 79 with petrelintide 7·0 mg, 82 with petrelintide 9·0 mg, and 81 with placebo. 255 (53%) participants were female, 230 (47%) were male, mean age was 47 (SD 12) years, mean bodyweight 107·1 kg (20·3), mean BMI 36·7 kg/m 2 (5·5), and 419 (86%) were White. Mean percentage change in bodyweight from baseline after 28 weeks (efficacy estimand) was -7·9% (95% CI -9·0 to -6·7) with petrelintide 1·0 mg, -7·9% (-9·0 to -6·7) with petrelintide 2·5 mg, -9·8% (-10·9 to -8·6) with petrelintide 5·0 mg, -9·3% (-10·5 to -8·2) with petrelintide 7·0 mg, and -9·4% (-10·5 to -8·3) with petrelintide 9·0 mg versus -1·7% (-2·8 to -0·5) with placebo. Estimated treatment differences versus placebo were -6·2% (-7·9 to -4·5) with petrelintide 1·0 mg, -6·2% (-7·8 to -4·5) with petrelintide 2·5 mg, -8·1% (-9·7 to -6·5) with petrelintide 5·0 mg, -7·7% (-9·3 to -6·0) with petrelintide 7·0 mg, and -7·7% (-9·4 to -6·1) with petrelintide 9·0 mg. Bodyweight continued to decline to week 42, with reductions of up to -10·7% with petrelintide. The most common adverse event with petrelintide was nausea (79 [20%] of 404 participants vs five [6%] participants with placebo). Vomiting was infrequent with petrelintide (12 [3%] participants vs five [6%] with placebo); active treatment and placebo had similarly low rates for diarrhoea (30 [7%] participants vs six [7%] with placebo) and constipation (28 [7%] vs three [4%] with placebo). No deaths were reported. Interpretation Petrelintide achieved clinically meaningful weight reduction and had similar gastrointestinal tolerability to that of placebo apart from predominantly mild nausea during dose escalation, supporting further evaluation as a long-term obesity therapy. Funding Zealand Pharma.