Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.

Finan, Brian; Ma, Tao; Ottaway, Nickki; Müller, Timo D; Habegger, Kirk M; Heppner, Kristy M; Kirchner, Henriette; Holland, Jenna; Hembree, Jazzminn; Raver, Christine; Lockie, Sarah H; Smiley, David L; Gelfanov, Vasily; Yang, Bin; Hofmann, Susanna; Bruemmer, Dennis; Drucker, Daniel J; Pfluger, Paul T; Perez-Tilve, Diego; Gidda, Jaswant; Vignati, Louis; Zhang, Lianshan; Hauptman, Jonathan B; Lau, Michele; Brecheisen, Mathieu; Uhles, Sabine; Riboulet, William; Hainaut, Emmanuelle; Sebokova, Elena; Conde-Knape, Karin; Konkar, Anish; DiMarchi, Richard D; Tschöp, Matthias H     «

Finan, Brian; Ma, Tao; Ottaway, Nickki; Müller, Timo D; Habegger, Kirk M; Heppner, Kristy M; Kirchner, Henriette; Holland, Jenna; Hembree, Jazzminn; Raver, Christine; Lockie, Sarah H; Smiley, David L; Gelfanov, Vasily; Yang, Bin; Hofmann, Susanna; Bruemmer, Dennis; Drucker, Daniel J; Pfluger, Paul T; Perez-Tilve, Diego; Gidda, Jaswant; Vignati, Louis; Zhang, Lianshan; Hauptman, Jonathan B; Lau, Michele; Brecheisen, Mathieu; Uhles, Sabine; Riboulet, William; Hainaut, Emmanuelle; Sebokova, Elena;...     »

We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.     «

We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rod...     »