Taspoglutide, an Analog of Human Glucagon-Like Peptide-1 with Enhanced Stability and in Vivo Potency

Taspoglutide is a novel analog of human glucagon-like peptide-1 [hGLP-1(7-36)NH2] in clinical development for the treatment of type 2 diabetes. Taspoglutide contains alpha-aminoisobutyric acid substitutions replacing Ala(8) and Gly(35) of hGLP-1(7-36) NH2. The binding affinity [radioligand binding assay using [(125)I]hGLP-1(7-36)NH2], potency (cAMP production in CHO cells stably over-expressing hGLP-1 receptor), and in vitro plasma stability of taspoglutide compared with hGLP-1(7-36) NH2 have been evaluated. Effects on basal and glucose-stimulated insulin secretion were determined in vitro in INS-1E cells and in vivo in normal rats. Taspoglutide has comparable affinity (affinity constant 1.1 +/- 0.2 nM) to the natural ligand (affinity constant 1.5 +/- 0.3 nM) for the hGLP-1 receptor and exhibits comparable potency in stimulating cAMP production (EC(50) Taspo 0.06 nM and EC(50)hGLP-1(7-36)NH20.08 nM). Taspoglutide exerts insulinotropic action in vitro and in vivo and retains the glucoincretin property of hGLP-1(7-36) NH2. Stimulation of insulin secretion is concentration dependent and evident in the presence of high-glucose concentrations (16.7 mM) with a taspoglutide concentration as low as 0.001 nM. Taspoglutide is fully resistant to dipeptidyl peptidase-4 cleavage (during 1 h incubation at room temperature with purified enzyme) and has an extended in vitro plasma half-life relative to hGLP-1(7-36) NH2 (9.8 h vs. 50 min). In vitro, taspoglutide does not inhibit dipeptidyl peptidase-4 activity. This study provides the biochemical and pharmacological basis for the sustained plasma drug levels and prolonged therapeutic activity seen in early clinical trials of taspoglutide. Excellent stability and potency with substantial glucoincretin effects position taspoglutide as a promising new agent for treatment of type 2 diabetes. (Endocrinology 151: 2474-2482, 2010)