Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dual glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide‐1 agonist RG7697 after single subcutaneous administration in healthy subjects

Abstract

Single s.c. injections of RG7697 up to 3.6 mg were generally well tolerated. Evidence of glycaemic effect and pharmacokinetic profiles consistent with once-daily dosing render this drug candidate suitable to be further tested in multiple-dose clinical trials in patients with type 2 diabetes.

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…In preclinical evaluation in diet-induced obese and diabetic, leptin-deficient db/db mice, each of these coagonists demonstrated superior weight-lowering and enhanced improvement of insulin resistance and glucose control relative to pharmacokinetically-matched, best-in-class GLP-1 monoagonists (Finan et al, 2013). Glycemic improvements as expected were achieved through enhanced insulinotropic efficacy, and this notably translated from rodent models of obesity to nonhuman primates and humans (Finan et al, 2013;Portron et al, 2017;Schmitt et al, 2017). Notably, weight loss induced by this twincretin peptide was mediated by inhibition of food intake with no effects on energy expenditure (Finan et al, 2013).…”

Incretins in obesity and diabetes

“…The widespread distribution of the GLP-1R throughout different tissues suggests that GLP-1 has other physiological effects in addition to glucose regulation. [125][126][127] This dual incretin receptor concept was recently reviewed. [102][103][104] GLP-1 stimulates insulin secretion in a glucose concentration-dependent manner at glucose level above 4.3 mmol/L (77 mg/dL).…”

“…124 Recently, there has been significant interest in developing unimolecular dual agonists of GIPR and GLP-1R (dual incretin receptor) with activity at each constitutive receptor. [125][126][127] This dual incretin receptor concept was recently reviewed. 121…”

“…Recently, there has been a surge in interest in developing unimolecular dual agonists of GIPR and GLP-1R with activity at both incretin receptors for even greater glucoselowering effects than seen with GLP-1R agonists alone. [125][126][127] A randomized, placebo-controlled and active comparator-controlled Phase II trial was reported for one of these dual incretin receptor agonists, LY3298176, in patients with type 2 diabetes. After 26 weeks, LY3298176 showed superior A1c control with greater weight loss and acceptable tolerability profile, compared with dulaglutide.…”

Therapeutic Potential of Lentivirus-Mediated Glucagon-Like Peptide-1 Gene Therapy for Diabetes

“…16 GLP-1 analogs (e.g., exenatide and liraglutide) are currently used in the treatment of T2DM. 17,18 However, incretinbased treatments manifest some concerning sideeffects. 19 Exenatide and liraglutide have been suspected to cause pancreatitis and pancreas cancer in addition to their observed gastrointestinal side effects.…”