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

• Published in: Science translational medicine Vol. 5; no. 209; p. 209ra151
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 30-10-2013
• Subjects: Acylation - drug effects; Adolescent; Adult; Aged; Animals; Diabetes Mellitus, Type 2 - drug therapy; Female; Gastric Inhibitory Polypeptide - administration & dosage; Gastric Inhibitory Polypeptide - pharmacology; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Haplorhini - metabolism; Humans; Hyperglycemia - drug therapy; Incretins - administration & dosage; Incretins - pharmacology; Incretins - therapeutic use; Insulin - metabolism; Liraglutide; Male; Mice; Middle Aged; Peptides - pharmacology; Rats; Receptors, Gastrointestinal Hormone; Receptors, Glucagon - agonists; Receptors, Glucagon - metabolism; Rodentia - metabolism; Treatment Outcome; Venoms - pharmacology; Weight Loss - drug effects; Young Adult
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.3007218

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.