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/m2 .

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.

• Authors: Rie Yazawa, Masahiro Ishida, Yesilda Balavarca, Anita M Hennige
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 25 Issue 7 Pg. 1973-1984 (07 2023) ISSN: 1463-1326 [Electronic] England
• PMID: 36974349 (Publication Type: Clinical Trial, Phase I, Randomized Controlled Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 Boehringer Ingelheim and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Chemical References

• BI 456906
• Blood Glucose
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Receptors, Glucagon

Topics

• Humans
• Male
• Blood Glucose
• Diabetes Mellitus, Type 2 (drug therapy)
• Double-Blind Method
• East Asian People
• Glucagon-Like Peptide-1 Receptor (agonists)
• Hypoglycemic Agents (therapeutic use)
• Obesity (complications, drug therapy)
• Overweight (complications, drug therapy)
• Receptors, Glucagon (agonists)