A Glycosylated Fc‐fused Glucagon‐like Peptide‐1 Receptor Agonist Exhibits Equivalent Glucose Lowering to but Fewer Gastrointestinal Side Effects Than Dulaglutide

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 < .01) or QT interval changes (mean at 14-20 hours, mSc: 0.28 mg/kg GLP-1-gFc, 0.0-8.0 vs. 0.07 mg/kg dulaglutide, 8.0-27.7; n.s.), observed as safety variables in rats and monkeys, compared with those of dulaglutide. Glucose reductions in an oral glucose tolerance test were significant at day 3 postdose 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 receptor agonist with better safety than dulaglutide to maximize therapeutic benefits in subjects with type 2 diabetes.