A randomized Phase I study of the safety, tolerability, pharmacokinetics and pharmacodynamics of BI 456906, a dual glucagon receptor/glucagon‐like peptide‐1 receptor agonist, in healthy Japanese men with overweight/obesity

Abstract Aim To report a Phase I study of subcutaneous glucagon receptor (GCGR)/glucagon‐like peptide‐1 receptor (GLP‐1R) dual agonist BI 456906 versus placebo in healthy Japanese men with overweight/obesity. Materials and methods We investigated multiple rising doses of BI 456906 escalated over 16 weeks (maximum doses: 1.8 mg once weekly [dose group {DG} 1], 4.8 mg once weekly [DG 2] and 2.4 mg twice weekly [DG 3]) in Japanese men with a body mass index of 23 to 40 kg/m 2 . Results Thirty‐six participants were treated (n = 9 per DG and placebo). Overall, 10 participants (37.0%) treated with BI 456906 withdrew from dose escalation due to adverse events (amylase increase, n = 1; decreased appetite, n = 9), and the proportion of participants was higher in DG 2 (n = 6, 66.7%) versus DGs 1 and 3 (both n = 2, 22.2%). No participants receiving placebo withdrew from dose escalation. BI 456906 exposure increased with dose and dose escalation in each DG. Treatment with BI 456906 decreased placebo‐corrected bodyweight after 16 weeks (placebo +1.06%): DG 1, −5.57%; DG 2, −12.37%; DG 3, −9.62%. Paracetamol absorption decreased in Week 1 for DGs 2 and 3, indicating transient delayed gastric emptying. BI 456906 reduced plasma alanine and glucagon levels, indicating indirect target engagement at GCGRs and GLP‐1Rs. Drug‐related adverse events were reported for all participants receiving BI 456906 and four receiving placebo, the most frequent being decreased appetite (n = 24, 66.7%). Conclusions BI 456906 showed no unexpected tolerability concerns and it reduced placebo‐corrected bodyweight by up to 12.37% in Japanese men with overweight/obesity after 16 weeks of treatment.