A randomized phase I study of BI 1820237, a novel neuropeptide Y receptor type 2 agonist, alone or in combination with low‐dose liraglutide in otherwise healthy men with overweight or obesity.

Aims: Pharmacotherapeutic options for obesity treatment include glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP‐1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G‐protein‐coupled Y receptors and represent attractive targets for modulating bodyweight. Materials and Methods: This first‐in‐human, three‐part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low‐dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075–2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025–1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug‐related AEs. Secondary endpoints are tolerability, PK and PD. Results: In total, 95 otherwise healthy men with increased BMI (25.0–34.9 kg/m2) were randomized. Drug‐related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug‐related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post‐dose paracetamol PK suggested that BI 1820237 and low‐dose liraglutide exhibited additive effects on gastric emptying. Conclusions: BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive. [ABSTRACT FROM AUTHOR]