Robust anti‐obesity and metabolic effects of a dual GLP‐1/glucagon receptor peptide agonist in rodents and non‐human primates

Abstract

AimsTo characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon‐like peptide‐1 (GLP‐1) and glucagon receptors.Materials and methods MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP‐1 or glucagon receptors, to potentiate glucose‐stimulated insulin secretion (GSIS) in pancreatic β‐cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes. The ability of MEDI0382 to reduce body weight and improve energy balance (i.e. food intake and energy expenditure), as well as control blood glucose, was evaluated in mouse models of obesity and healthy cynomolgus monkeys following single and repeated daily subcutaneous administration for up to 2 months.Results MEDI0382 potently activated rodent, cynomolgus and human GLP‐1 and glucagon receptors and exhibited a fivefold bias for activation of GLP‐1 receptor versus the glucagon receptor. MEDI0382 produced superior weight loss and comparable glucose lowering to the GLP‐1 peptide analogue liraglutide when administered daily at comparable doses in DIO mice. The additional fat mass reduction elicited by MEDI0382 probably results from a glucagon receptor‐mediated increase in energy expenditure, whereas food intake suppression results from activation of the GLP‐1 receptor. Notably, the significant weight loss elicited by MEDI0382 in DIO mice was recapitulated in cynomolgus monkeys.ConclusionsRepeated administration of MEDI0382 elicits profound weight loss in DIO mice and non‐human primates, produces robust glucose control and reduces hepatic fat content and fasting insulin and glucose levels. The balance of activities at the GLP‐1 and glucagon receptors is considered to be optimal for achieving weight and glucose control in overweight or obese Type 2 diabetic patients.

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…To a lesser magnitude relative to what was observed in obese wild-type mice, the dual agonist also lowered body weight in mice lacking the GLP-1 receptor, thus corroborating that GcgR agonism is a valuable constituent to the combined pharmacology (Day et al, 2009). Of appreciable note, GLP-1/ glucagon dual agonism also effectively lowers body weight and improves glycemia in nonhuman primates (Tschop et al, 2016), an important observation later also confirmed with another GLP-1/glucagon dual agonist (Henderson et al, 2016). Another interesting and unexpected finding was the ability of such a dual agonist to improve leptin sensitivity of DIO mice, despite continued chronic exposure of the mice to a high-sugar HFD .…”

“…The initial 2009 coagonist report was received with healthy scientific skepticism, but the independent confirmation at other research sites and the translation from obese rodents to nonhuman primates have supported the advancement of the concept to human studies (Day et al, 2009Pocai et al, 2009;Henderson et al, 2016). Separately, low-dose coinfusion of GLP-1 and glucagon has been demonstrated to decrease food intake (Cegla et al, 2014) and to increase energy expenditure in humans (Tan et al, 2013).…”

“…Following their introduction in 2009 (Day et al, 2009), several dual agonists targeting the receptors for GLP-1 and glucagon have been developed (Fig. 3) and their efficacy translates from obese rodents to nonhuman primates and humans (Day et al, 2009;Pocai et al, 2009;Henderson et al, 2016;Tschop et al, 2016;Evers et al, 2017).…”

Running on mixed fuel‐dual agonistic approach of GLP‐1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non‐human primates

“…Similarly, Lao et al reported that their dual GLP‐1R/GCGR agonist showed higher weight loss in diet‐induced obese rhesus monkeys and better glucose control in diabetic rhesus monkeys than GLP‐1R agonist gold standard liraglutide . A recent report also indicates that administration of MEDI0382, a dual GLP‐1R/GCGR agonist, at toxicological doses, to lean and healthy cynomolgus monkeys led to significant reduction in body weight . The impact on body weight results from a significant suppression of energy intake but may also arise from increased energy expenditure as observed in a sub‐chronic study in rats, in a multiple dosing study for 4 weeks in DIO mice and in humans .…”

Twincretin as a potential therapeutic for the management of type 2 diabetes with obesity

“…Recently, several GLP‐1/GR dual agonists have been under development (Table ). Preclinical studies showed that the GLP‐1R/GR dual agonist, SAR425899 (Sanofi, Paris, France), decreased bodyweight in diet‐induced obese mice and ameliorated glucose levels in db / db mice, and that the GLP‐1R/GR dual agonist, MEDI0382 (MedImmune, Gaithersburg, MD, USA), significantly reduced bodyweight and improved glucose tolerance to levels similar to those obtained by the GLP‐1R agonist, liraglutide, in non‐human primates. Based on the promising results with GLP‐1R/GIPR and GLP‐1R/GR dual agonists, GLP‐1R/GIPR/GR triple agonists also have been under development as therapeutics for type 2 diabetes (Table ).…”