The limitation of lipidation: Conversion of semaglutide from once-weekly to once-monthly dosing

The objective of this work was to develop a long-acting form of the lipidated peptide semaglutide that can be administered to humans once-monthly. Semaglutide was attached to hydrogel microspheres by a cleavable linker with an expected in vivo release half-life of about 1 mo. After a single subcutaneous dose, the pharmacokinetic parameters of released semaglutide and bodyweight loss were determined in mice, and results were used to estimate the dosing and pharmacokinetics of the released semaglutide in humans. The in vivo half-life of released semaglutide was ~36 d, and a single dose in diet-induced obese mice resulted in a lean-sparing body weight loss of 20% over 1 mo, statistically the same as semaglutide dosed twice daily. Simulations indicated the microsphere-semaglutide would permit once-monthly administration in humans; moreover, it could maintain the therapeutic minimum concentration (C min ) of once-weekly semaglutide with only 75% of the once-weekly maximum concentration (C max ), a feature that could reduce adverse side effects or allow higher dosing. The same approach should enable the conversion of other lipidated peptides from once-weekly to once-monthly administration.