A glycosylated Fc-fused GLP-1 exhibits equivalent glucose lowering effect but lesser gastrointestinal side effect than Dulaglutide.

AIMS: Despite their attractiveness as novel antidiabetic agents, GLP-1 receptor agonists (GLP-1 RAs) have provided limited therapeutic benefits due to common drug nonadherence, due mainly to side effects such as nausea, vomiting, and abdominal pain. Considering different GLP-1 receptor density throughout the organs, binding modulation to change receptor binding mechanism could be tried for the invention of novel GLP-1 RAs with better safety profile.

MATERIALS AND METHODS: We constructed a novel glycosylated Fc-fused GLP-1 RA (GLP-1-gFc) and determined binding affinity and potency using in-vitro instrumental and cell-based analyses followed by in-vivo comparison of glucose-lowering and 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 times less binding affinity and 4 times less potency than dulaglutide in in-vitro. A potency-adjusted dose delayed HbA1c increase comparable to that of dulaglutide (Change % for 6 weeks: 2.4 mg/kg GLP-1-gFc, 4.34 ± 0.40 versus 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 versus 0.6 mg/kg dulaglutide, 0.04 ± 0.01; p < 0.01) or QT interval changes (mean at 14 h - 20 h, mSc: 0.28 mg/kg GLP-1-gFc, 0.0-8.0 versus 0.07 mg/kg dulaglutide, 8.0-27.7; n.s.), observed as safety parameters in rats and monkeys, compared to those of dulaglutide. Glucose reductions in an oral glucose tolerance test were significant at day 3 post-dose without severe gastrointestinal adverse events and pulse rate changes in healthy subjects.

CONCLUSIONS: These results suggest that GLP-1-gFc could be used as a novel GLP-1 RA with better safety than dulaglutide to maximize therapeutic benefits in subjects with type 2 diabetes. This article is protected by copyright. All rights reserved.