Preclinical Effects of Efpeglenatide, a Long-Acting Glucagon-Like Peptide-1 Receptor Agonist, Compared with Liraglutide and Dulaglutide

Efpeglenatide (efpeg) is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) in development for type 2 diabetes. The effects of efpeg vs. those of liraglutide (lira) and dulaglutide (dula) on glucodynamics and weight/lipid profiles were studied over 4 weeks in mouse models of diabetes (db/db) and obesity (diet-induced obesity DIO), respectively; doses tested wereefpeg 1.45, 2.89, or 4.35 nmol/kg once every 2 days (Q2D); twice-daily lira 30 nmol/kg (db/db study) or 50 nmol/kg (DIO study); dula 0.98 or 1.96 nmol/kg Q2D (equivalent human doses/key results in Table). At the highest doses tested, efpeg was significantly more effective at lowering blood glucose (vs. lira and dula) and reducing the increase in glycated hemoglobin (HbA1c) from Day 0 (vs. lira) in db/db mice. Efpeg also improved insulin sensitivity (vs. lira and dula) and postprandial glucose control (vs. dula). In DIO mice, efpeg significantly reduced body weight and mesenteric fat mass (vs. dula), and cholesterol (vs. lira and dula; at highest doses). Overall, efpeg showed greater reductions in blood glucose, HbA1c increase, weight, and cholesterol vs. other GLP-1 RAs in mice. These effects may be due to the distinct receptor binding properties of efpeg, which enhance intracellular signaling and insulin release in β-cells. Further studies are needed to assess the clinical relevance of these findings. Disclosure M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.