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A glycosylated Fc-fused glucagon-like peptide-1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide.


ABSTRACT: AIM:To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc-fused glucagon-like peptide-1(GLP-1-gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP-1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans. MATERIALS AND METHODS:We constructed GLP-1-gFc and determined its binding affinity and potency using in vitro instrumental and cell-based analyses followed by in vivo comparison of the glucose-lowering and gastrointestinal side effects between GLP-1-gFc and dulaglutide. A phase 1 clinical trial was conducted to confirm the efficacy and safety profile of GLP-1-gFc. RESULTS:GLP-1-gFc showed 10-fold less binding affinity and 4-fold less potency than dulaglutide in in vitro. A potency-adjusted dose delayed HbA1c increase comparable with that of dulaglutide (Change for 6?weeks: 2.4?mg/kg GLP-1-gFc, 4.34?±?0.40 vs. 0.6?mg/kg dulaglutide, 4.26?±?0.22; n.s.). However, the equivalent efficacy dose and higher dose did not induce malaise-related responses (blueberry bar consumption, g/mouse: 2.4?mg/kg GLP-1-gFc, 0.15%?±?0.03% vs. 0.6?mg/kg dulaglutide, 0.04%?±?0.01%; P?

SUBMITTER: An IB 

PROVIDER: S-EPMC7383507 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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A glycosylated Fc-fused glucagon-like peptide-1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide.

An In Bok IB   Byun Mi Sun MS   Yang Sang In SI   Choi Yuri Y   Woo Jung Won JW   Jang Hak Chul HC   Sung Young Chul YC  

Diabetes, obesity & metabolism 20200603 8


<h4>Aim</h4>To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc-fused glucagon-like peptide-1(GLP-1-gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP-1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans.<h4>Materials and methods</h4>We constructed GLP-1-gFc and determined its binding affinity and potency using in vitro instr  ...[more]

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