Abstract 4116298: Once Weekly Utreglutide (GL0034), a Glucagon-like Peptide-1 Receptor Agonist, at 4 × 450 µg Doses Reduces Blood Pressure, Lipids, and Body Weight in Post-menopausal Females: A Phase I Study

Background: Utreglutide (GL0034), a novel, once weekly glucagon-like peptide-1 receptor agonist (GLP-1RA), previously demonstrated significant reductions in body weight (BW) after a single dose ascending study in individuals with obesity . BW reductions after pharmacological treatment of obesity with GLP-1RA is associated with blood pressure (BP) lowering effects. Aim: This phase I study assessed the safety, tolerability, and cardio-metabolic effects of utreglutide after multiple ascending doses in post-menopausal female volunteers with overweight and obesity. Methods: In this randomized, double-blind, placebo-controlled study 12 post-menopausal female volunteers with overweight/obesity, aged 18 to 65 years old with a body mass index (BMI) ≥26 kg/m 2 were randomized (9:3) to subcutaneous utreglutide fixed doses (4 × 450 µg); or placebo once weekly for four weeks. Safety, tolerability, and key cardio-metabolic parameters were assessed. Biomarker measurements included oral glucose tolerance test (OGTT) insulin and glucose area under the curve (AUC), systolic- and diastolic BP, lipid profile (triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL), creatinine, potassium, BW and leptin. Results: Utreglutide was generally well tolerated and related adverse effects were mainly gastrointestinal with dose-dependent nausea, vomiting and decreased appetite. Reductions in OGTT AUCs of insulin ( p <0.05) and glucose ( p <0.01) were noted on Day 23 after four weeks treatment with Utreglutide. This was accompanied by a decrease ( p <0.001) in mean systolic and diastolic BP on Day 23 from baseline (BL). On Day 23, significant reductions in TC ( p <0.01), LDL ( p <0.05) and non-HDL ( p <0.05) were observed. BW reduction versus BL ( p <0.001) was 2.0 kg and 1.8 kg respectively on Day 29 and End of Study (EoS). Leptin levels significantly reduced from BL on Day 23 ( p< 0.01) and EoS ( p <0.001). No significant changes were observed for TG, creatinine and potassium (Table). Conclusions: Once weekly utreglutide dosing for four weeks at a dose of 450 µg in post-menopausal females with overweight and obesity, demonstrated clinically relevant reductions of systolic and diastolic BP. This was associated with improved performance of OGTT AUC of insulin and glucose, lipids, BW and leptin with an overall good tolerability and with potential to demonstrate cardio-metabolic benefits.