Phase I studies of the safety, tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor/glucagon-like peptide-1 receptor agonist BI 456906.

Abstract

AIM:

To report two phase I studies of the novel subcutaneous glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonist BI 456906 versus placebo in healthy volunteers and people with overweight/obesity.

MATERIALS AND METHODS:

A phase Ia study (NCT03175211) investigated single rising doses (SRDs) of BI 456906 in 24 males with a body mass index (BMI) of 20-<30 kg/m2 . A phase Ib study (NCT03591718) investigated multiple rising doses (MRDs) of BI 456906 (escalated over 6 [Part A] or 16 [Part B] weeks) in 125 adults with a BMI of 27-40 kg/m2 .

RESULTS:

In the SRD study (N = 24), mean body weight decreased with increasing BI 456906 dose. In the MRD study, the maximum decreases in placebo-corrected mean body weight were at week 6 (-5.79%, dosage schedule [DS] 1; Part A) and week 16 (-13.8%, DS7; Part B). BI 456906 reduced plasma amino acids and glucagon, indicating target engagement at GCGRs and GLP-1Rs. Drug-related adverse events (AEs) increased with BI 456906 dose. The most frequent drug-related AE with SRDs was decreased appetite (n = 9, 50.0%), and two subjects (8.3%) did not complete the trial because of AEs (nausea and vomiting). During MRD Part A (N = 80), 10 subjects (12.5%) discontinued BI 456906, most commonly because of a cardiac or vascular AE (n = 6, 7.5%); during Part B (N = 45), eight subjects (17.8%) discontinued BI 456906, mainly because of AEs (n = 6, 13.3%), most commonly gastrointestinal disorders.

CONCLUSIONS:

BI 456906 produced a placebo-corrected body weight loss of 13.8% (week 16), highlighting its potential to promote clinically meaningful body weight loss in people with overweight/obesity.

• Authors: Arvid Jungnik, Jorge Arrubla Martinez, Leona Plum-Mörschel, Christoph Kapitza, Daniela Lamers, Claus Thamer, Corinna Schölch, Michael Desch, Anita M Hennige
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 25 Issue 4 Pg. 1011-1023 (04 2023) ISSN: 1463-1326 [Electronic] England
• PMID: 36527386 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Boehringer Ingelheim and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Chemical References

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

Topics

• Adult
• Male
• Humans
• Glucagon-Like Peptide 1 (therapeutic use)
• Hypoglycemic Agents (therapeutic use)
• Diabetes Mellitus, Type 2 (drug therapy)
• Receptors, Glucagon (agonists)
• Glucagon-Like Peptide-1 Receptor (agonists)
• Overweight (drug therapy)
• Blood Glucose (metabolism)
• Body Weight
• Obesity (drug therapy)
• Weight Loss
• Double-Blind Method