Creating Glepaglutide, the First Long-Acting GLP-2 Analogue to Enable a Ready-to-Use Injection

Abstract

Human glucagon-like peptide-2 (hGLP-2) receptor agonists have a benefit for the treatment of short bowel syndrome (SBS) and potentially other intestinal diseases (e.g., IBD). Native hGLP-2, a 33-amino acid gastrointestinal hormone, has a short half-life and is chemically and physically unstable, rendering it unsuitable for clinical use. In this paper, we describe the design of novel hGLP-2 peptide analogues with significantly improved chemical and physical properties, high in vitro hGLP-2 receptor potencies, and extended half-lives. Furthermore, synthesis yields were significantly improved by the addition of a C-terminal (lysine)₆ tail (Structure Inducing Probe technology, SIP). One hGLP-2 analogue described herein is glepaglutide ([Gly²Glu³Thr⁵Ser⁸Leu¹⁰Ala^11,16,24,28] hGLP-2[1–33]-NH-[Lys]6-NH₂), the first long-acting analogue with excellent physicochemical stability, making it suitable for liquid formulation. Glepaglutide is currently in phase 3 clinical trials as a potential new therapy for SBS and is the only hGLP-2 analogue in clinical testing that is dosed subcutaneously from a ready-to-use formulation in an autoinjector.