First-in-human study of a pharmacological duodenal exclusion therapy shows reduced postprandial glucose and insulin and increased bile acid and gut hormone concentrations.
GLP-1
bariatric surgery
clinical trial
drug development
pharmacodynamics
type 2 diabetes
Journal
Diabetes, obesity & metabolism
ISSN: 1463-1326
Titre abrégé: Diabetes Obes Metab
Pays: England
ID NLM: 100883645
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
14
03
2023
received:
20
01
2023
accepted:
22
03
2023
medline:
3
8
2023
pubmed:
29
6
2023
entrez:
28
6
2023
Statut:
ppublish
Résumé
To address the need for noninvasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity by developing an orally administered therapeutic polymer, GLY-200, designed to bind to and enhance the barrier function of mucus in the gastrointestinal tract to establish duodenal exclusion noninvasively. A Phase 1, randomized, double-blind, placebo-controlled, single- (SAD) and multiple-ascending-dose (MAD) healthy volunteer study was conducted. In the SAD arm, four cohorts received a single dose of 0.5 g up to 6.0 g GLY-200 or placebo, while in the MAD arm, four cohorts received 5 days of twice-daily or three-times-daily dosing (total daily dose 2.0 g up to 6.0 g GLY-200 or placebo). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics, including serum glucose, insulin, bile acids and gut hormones. No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. In the MAD arm (Day 5), reductions in glucose and insulin and increases in bile acids, glucagon-like peptide-1, peptide YY and glicentin, were observed following a nonstandardized meal in subjects receiving twice-daily dosing of 2.0 g GLY-200 (N = 9) versus those receiving placebo (N = 8). GLY-200 is safe and generally well tolerated at doses of ≤2.0 g twice daily. Pharmacodynamic results mimic the biomarker signature observed after Roux-en-Y gastric bypass and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine. This study represents the first clinical demonstration that duodenal exclusion can be achieved with an oral drug and supports further development of GLY-200 for the treatment of obesity and/or T2D.
Substances chimiques
Insulin
0
Bile Acids and Salts
0
Blood Glucose
0
Insulin, Regular, Human
0
Glucose
IY9XDZ35W2
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2447-2456Informations de copyright
© 2023 Glyscend Therapeutics. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
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