Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Petrelintide for Weight Management: Two Randomized, Controlled Phase 1 Trials

AIMS: Petrelintide is a long-acting amylin analogue in development for weight management. The safety, tolerability, pharmacokinetics, and pharmacodynamics of petrelintide were evaluated in single ascending dose (SAD) and multiple ascending dose (MAD) trials. MATERIALS AND METHODS: Both trials were randomized, placebo-controlled, and double-blind. The SAD trial assessed subcutaneous (SC) petrelintide doses of 0.04-2.4 mg and a 0.35 mg intravenous dose. The MAD trial evaluated 6 once-weekly SC doses of 0.6 and 1.2 mg (part 1), and 16 once-weekly doses escalated every 2 weeks to target doses of 2.4, 4.8, and 9.0 mg (part 2). The SAD and MAD part 1 trials enrolled normal or overweight adults; MAD part 2 enrolled adults with overweight or obesity. RESULTS: Petrelintide was well tolerated, with no serious or severe treatment-emergent adverse events (TEAEs). In both trials, the most common TEAEs included gastrointestinal (GI) disorders, most of which were mild. One participant discontinued treatment due to GI TEAEs. Nausea, the most common GI TEAE, occurred in 16.7%-33.3% of participants receiving petrelintide versus 16.7% for placebo in MAD part 2, while diarrhoea was rare and vomiting was only experienced by the participant who discontinued. Petrelintide was slowly absorbed, had a half-life of ~10 days, showed steady-state dose proportionality, and reduced body weight by up to 8.6% after 16 weeks. CONCLUSION: Petrelintide appeared safe, had a low incidence of GI TEAEs, and resulted in clinically relevant weight loss. These findings support further development of petrelintide as an effective weight-management medication, with potential for improved GI tolerability over existing therapies.