Efficacy and safety of the ghrelin-O-acyltransferase inhibitor BI 1356225 in overweight/obesity: Data from two Phase I, randomised, placebo-controlled studies.
Appetite
Ghrelin
Ghrelin-O-acyltransferase
Pharmacodynamics
Pharmacokinetics
Tolerability
Journal
Metabolism: clinical and experimental
ISSN: 1532-8600
Titre abrégé: Metabolism
Pays: United States
ID NLM: 0375267
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
27
09
2022
revised:
10
03
2023
accepted:
15
03
2023
medline:
2
5
2023
pubmed:
24
3
2023
entrez:
23
3
2023
Statut:
ppublish
Résumé
Obesity is a complex disease associated with multiple concurrent complications, and the coordinated targeting of multiple pathways in pharmacological treatment may improve weight loss outcomes. During synthesis, ghrelin is converted from the 'inactive' unacylated ghrelin (UAG) to the active acylated ghrelin (AG) by the enzyme ghrelin-O-acyltransferase (GOAT), stimulating appetite and food intake. To report the results of two Phase I studies investigating single rising doses (SRDs) or multiple rising doses (MRDs) of the novel oral GOAT inhibitor BI 1356225 versus placebo in male and postmenopausal/sterilised female subjects with overweight or obesity. The SRD study investigated single doses of BI 1356225 (0.1-20.0 mg) in healthy male subjects with a BMI of 18.5-29.9 kg/m Sixty-five subjects were treated in the SRD study. Drug-related adverse events (AEs) were reported for five subjects (9.1 %) in the SRD cohort and two subjects (20.0 %) in the BA cohort, with the most frequent being headache (SRD: n = 4, 9.8 %; BA: n = 1, 10.0 %). In the MRD study, two (2.3 %) of the 87 subjects treated discontinued treatment because of AEs. Drug-related AEs were reported for 18 subjects (20.7 %), did not increase with dose and were most frequently reported as headache (n = 5, 5.7 %) and gastrointestinal disorders (n = 5, 5.7 %). In both studies, exposure parameters (area under the concentration-time curve [AUC] and maximum plasma concentration [C Treatment with SRDs and MRDs of BI 1356225 was well tolerated by healthy males and subjects with overweight/obesity. BI 1356225 treatment over 28 days reduced AG concentrations and the AG/UAG ratio by >80 %, but no effect was seen on bodyweight, hunger/satiety, control of eating or energy intake. Although, at 4 weeks, the MRD study was fairly short, a reduction in bodyweight would be expected to be evident by this time, suggesting that a reduction of AG via a GOAT inhibitor is not sufficient to induce clinically relevant bodyweight loss.
Sections du résumé
BACKGROUND
Obesity is a complex disease associated with multiple concurrent complications, and the coordinated targeting of multiple pathways in pharmacological treatment may improve weight loss outcomes. During synthesis, ghrelin is converted from the 'inactive' unacylated ghrelin (UAG) to the active acylated ghrelin (AG) by the enzyme ghrelin-O-acyltransferase (GOAT), stimulating appetite and food intake.
AIMS
To report the results of two Phase I studies investigating single rising doses (SRDs) or multiple rising doses (MRDs) of the novel oral GOAT inhibitor BI 1356225 versus placebo in male and postmenopausal/sterilised female subjects with overweight or obesity.
METHODS
The SRD study investigated single doses of BI 1356225 (0.1-20.0 mg) in healthy male subjects with a BMI of 18.5-29.9 kg/m
RESULTS
Sixty-five subjects were treated in the SRD study. Drug-related adverse events (AEs) were reported for five subjects (9.1 %) in the SRD cohort and two subjects (20.0 %) in the BA cohort, with the most frequent being headache (SRD: n = 4, 9.8 %; BA: n = 1, 10.0 %). In the MRD study, two (2.3 %) of the 87 subjects treated discontinued treatment because of AEs. Drug-related AEs were reported for 18 subjects (20.7 %), did not increase with dose and were most frequently reported as headache (n = 5, 5.7 %) and gastrointestinal disorders (n = 5, 5.7 %). In both studies, exposure parameters (area under the concentration-time curve [AUC] and maximum plasma concentration [C
CONCLUSIONS
Treatment with SRDs and MRDs of BI 1356225 was well tolerated by healthy males and subjects with overweight/obesity. BI 1356225 treatment over 28 days reduced AG concentrations and the AG/UAG ratio by >80 %, but no effect was seen on bodyweight, hunger/satiety, control of eating or energy intake. Although, at 4 weeks, the MRD study was fairly short, a reduction in bodyweight would be expected to be evident by this time, suggesting that a reduction of AG via a GOAT inhibitor is not sufficient to induce clinically relevant bodyweight loss.
Identifiants
pubmed: 36958671
pii: S0026-0495(23)00153-1
doi: 10.1016/j.metabol.2023.155550
pii:
doi:
Substances chimiques
Acyltransferases
EC 2.3.-
Ghrelin
0
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
155550Informations de copyright
Copyright © 2023 Boehringer Ingelheim International GmbH. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest SB and DS are employees of Boehringer Ingelheim. BK, FS and TF are employees of CRS Clinical Research Services. AH is external employee of Boehringer Ingelheim. LH was contracted by Boehringer Ingelheim as an external statistician. TF has provided advisory services to AstraZeneca, Atrogi, Bayer, Cipla, Eli Lilly, Eyesense, Fortbildungskolleg, Novo Nordisk, Pfizer, Sanofi, Remynd and Roche. TF has provided speaker activities to Amarin, AstraZeneca, Boehringer Ingelheim, Berlin Chemie, Cipla, Daiichi-Sankyo, Eli Lilly, Fortbildungskolleg, MSD, Novartis, Novo Nordisk, Sanofi and Santis.