Petrelintide

Petrelintide (ZP-8396) is a long-acting, subcutaneously administered analog of human amylin developed by Zealand Pharma A/S (Soborg, Denmark) as a potential foundational therapy for chronic weight management in adults with overweight and obesity. The compound is a 36-amino-acid acylated peptide bearing a lactam bridge replacement of the native Cys2-Cys7 disulfide bond, N-methylations at Gly24 and Ile26 to prevent amyloid fibrillation, strategic asparagine deletions and substitutions to eliminate deamidation-prone residues, a C-terminal hydroxyproline substitution for enhanced receptor potency, and an N-terminal C20 diacid lipidation via a gamma-glutamic acid linker that confers reversible albumin binding and a human terminal half-life of approximately 10 days, supporting convenient once-weekly dosing. Petrelintide exhibits potent balanced agonism at the amylin-3 receptor (AMY3R, EC50 0.33 nM) and the calcitonin receptor (CTR, EC50 0.32 nM) in cAMP accumulation assays, classifying it as a dual amylin and calcitonin receptor agonist (DACRA). In diet-induced obese rat models, repeated dosing produces dose-dependent reductions in food intake and body weight with preferential fat mass loss and relative preservation of lean mass. Clinical development has progressed rapidly. A first-in-human Phase 1 single ascending dose trial (NCT05096598) established safety and tolerability at subcutaneous doses of 0.04 to 2.4 mg, with a human half-life supporting weekly administration. A Phase 1b multiple ascending dose trial in 48 participants with overweight or obesity demonstrated mean body weight reductions of 4.8% (2.4 mg), 8.6% (4.8 mg), and 8.3% (9.0 mg) versus 1.7% with placebo after 16 weekly doses, with no serious or severe adverse events and gastrointestinal tolerability substantially superior to the adverse-event profiles reported for GLP-1 receptor agonist monotherapy at comparable weight-loss magnitudes. The Phase 2 ZUPREME-1 trial (NCT06662539) in 493 adults with obesity met its primary endpoint across all five dose arms, achieving up to 10.7% mean body weight reduction at 42 weeks with placebo-like tolerability, zero vomiting at the maximally effective dose, and discontinuation rates due to adverse events comparable to placebo (4.8% versus 4.9%). In March 2025, Roche entered an exclusive global collaboration and licensing agreement with Zealand Pharma valued at up to 5.3 billion US dollars to co-develop and co-commercialize petrelintide as monotherapy and in fixed-dose combination with CT-388, a dual GLP-1/GIP receptor agonist. Phase 3 initiation for chronic weight management is planned for the second half of 2026. Petrelintide is an investigational compound; its safety and efficacy have not been established by any regulatory authority. This monograph reviews the peptide chemistry, receptor pharmacology, preclinical and clinical evidence base, pharmacokinetic profile, and comparative positioning of petrelintide within the amylin receptor agonist landscape, grounded in the primary literature through May 2026. Investigators should treat all data as preliminary pending registration-quality Phase 3 results and regulatory evaluation.