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

Mar 28, 2023Diabetes, obesity & metabolism

Safety and body effects of BI 456906, a drug targeting blood sugar and appetite hormones, in healthy overweight Japanese men

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Abstract

Treatment with BI 456906 reduced placebo-corrected bodyweight by up to 12.37% in Japanese men with overweight/obesity after 16 weeks.

Thirty-six participants were treated, with 10 (37.0%) withdrawing due to adverse events, predominantly decreased appetite.
The withdrawal rate was higher in the 4.8 mg dose group (66.7%) compared to the other dose groups (22.2%).
BI 456906 exposure increased with the dose and during dose escalation.
Treatment was associated with reduced plasma levels of alanine and glucagon, suggesting effective engagement with the targeted receptors.
Paracetamol absorption decreased in Week 1 for higher dose groups, indicating a potential delay in gastric emptying.

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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.

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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

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