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

Autor: Jungnik A; Boehringer Ingelheim Pharma GmbH, Biberach, Germany., Arrubla Martinez J; Profil Institute for Metabolic Research, Neuss, Germany., Plum-Mörschel L; Profil Mainz GmbH & Co. KG, Mainz, Germany., Kapitza C; Profil Institute for Metabolic Research, Neuss, Germany.; Profil Mainz GmbH & Co. KG, Mainz, Germany., Lamers D; Profil Institute for Metabolic Research, Neuss, Germany., Thamer C; Boehringer Ingelheim Pharma GmbH, Biberach, Germany., Schölch C; Boehringer Ingelheim Pharma GmbH, Biberach, Germany., Desch M; Boehringer Ingelheim Pharma GmbH, Biberach, Germany., Hennige AM; Boehringer Ingelheim International GmbH, Biberach, Germany.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2023 Apr; Vol. 25 (4), pp. 1011-1023. Date of Electronic Publication: 2023 Jan 30.
DOI: 10.1111/dom.14948
Abstrakt: 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/m 2 . 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/m 2 .
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.
(© 2022 Boehringer Ingelheim and The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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