First‐in‐Human Study of a Long‐Acting GLP‐1 Receptor Agonist (TE‐8105) in Overweight or Obese Adults Without Type 2 Diabetes Mellitus

Abstract Glucagon‐like peptide‐1 (GLP‐1) receptor agonists have revolutionized weight management and are becoming essential for the treatment of obesity‐related medical conditions. This study aimed to determine the pharmacokinetics, preliminary pharmacodynamics, safety, and tolerability of a long‐acting GLP‐1 receptor agonist, TE‐8105, in overweight or obese adults without T2DM. An open‐label study of four single ascending dose cohorts (A1‐A4, 0.5, 0.75, 1.5, and 3.0 mg TE‐8105, respectively) and two multiple dose cohorts (B1 flat dosing, 1.0 mg TE‐8105 Q2W SC for 5 doses, and B2 titration dosing, sequence 2 × 1.5, 2 × 2.0, 2 × 2.5, and 3 × 3.0 mg Q2W SC) was conducted using a combination of in‐patient and out‐patient assessments. The half‐life of TE‐8105 was about 120 h. There was no accumulation after flat dosing, but mean (SD) accumulation ratios were 3.75 (0.86) for C max and 3.00 (0.65) for AUC following titration dosing. The mean % decrease in body weight from baseline to the end of study visit for titration dosing was 2.06%, with 4/8 participants maintaining weight loss of ≥5%. Treatment‐related treatment emergent adverse effects (TEAEs) were consistent with the mechanism of action of TE‐8105 and dose‐dependent, including nausea (Part A: 16.7%; Part B: 21.4%), abdominal pain (Part A: 4.2%), constipation (Part A: 4.2%; Part B: 7.1%), and vomiting (Part A: 4.2%; Part B: 7.1%). Overall, TE‐8105 was safe and well tolerated with pharmacokinetics potentially allowing for less frequent SC dosing than currently available GLP‐1 receptor agonists.