Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans

Abstract

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.

Targeting the gastrointestinal tract to treat type 2 diabetes

“…For example, infusion of bombesin, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, or peptone stimulates the cosecretion of GLP-1, PYY, neurotensin and CCK , and interestingly, neurotensin acts synergistically with GLP-1 to regulate metabolism (Grunddal et al 2016). This suggests that stimulating the release of an endogenous gut peptide 'cocktail', similar to engineering poly-agonists that mimic these peptides (Day et al 2009, Finan et al 2013, could be a useful alternative approach for improving metabolic control in type 2 diabetes.…”

“…Combination therapy with long-acting GIP and GLP-1 mimetics has been considered in preclinical studies with some success (Irwin & Flatt 2009); however, issues of separate drug formulation and dosing limits the therapeutic success. As such, a single hybrid peptide, MAR701, has been developed that can directly activate both GIP receptor and GLP-1R and appears to have beneficial effects in rodents (Finan et al 2013).…”

Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

“…Another incretin pathway compound in early-stage development is a peptide that acts as an agonist at both the GLP-1 and GIP receptors (103). A preclinical study indicates that this dual agonist has the potential to enhance the antihyperglycemic and antiobesity effects observed with monoagonism because it affects adiposityinduced insulin resistance and pancreatic insulin deficiency.…”

The Novel GLP-1–Gastrin Dual Agonist ZP3022 Improves Glucose Homeostasis and Increases β-Cell Mass without Affecting Islet Number in db/db Mice

“…Interestingly, multifunctional peptides with agonistic properties toward not only the GLP-1 receptor but also other gastrointestinal hormone receptors such as glucagon or glucose-dependent insulinotropic polypeptide have been developed recently (Day et al, 2009;Pocai et al, 2009;Finan et al, 2013). These novel dual-acting peptides have highlighted possible synergistic effects of combining GLP-1 agonism with other gastrointestinal hormones as an effective treatment of T2D and/or obesity.…”