Endocrinology · Medical Literature
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 Cmax 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.
Clinical relevance
This first-in-human phase I study characterizes the pharmacokinetics, preliminary pharmacodynamics, safety, and tolerability of TE-8105, a novel long-acting GLP-1 receptor agonist, in overweight or obese adults without type 2 diabetes mellitus — a population with high unmet need for effective, convenient weight-management therapies. The study addresses a critical gap in the therapeutic landscape by exploring a dosing interval potentially less frequent than currently approved GLP-1 receptor agonists (e.g., weekly semaglutide), which may improve patient adherence and broaden access. Clinicians managing obesity and its cardiometabolic sequelae should be aware of this emerging agent as it advances through the development pipeline.
Key findings
1. Pharmacokinetic profile: TE-8105 demonstrated a half-life of approximately 120 hours (~5 days), supporting a subcutaneous every-2-week (Q2W) dosing regimen — longer than currently approved weekly GLP-1 receptor agonists. 2. Accumulation — flat dosing (Cohort B1, 1.0 mg Q2W × 5 doses): No drug accumulation was observed with flat dosing, suggesting predictable linear kinetics at this dose level. 3. Accumulation — titration dosing (Cohort B2: 2×1.5 mg, 2×2.0 mg, 2×2.5 mg, 3×3.0 mg Q2W SC): Mean (SD) accumulation ratios were 3.75 (0.86) for Cmax and 3.00 (0.65) for AUC, indicating significant dose-dependent drug accumulation with titration. 4. Weight loss — titration dosing cohort: Mean percent decrease in body weight from baseline to end-of-study visit was 2.06%, with 4 out of 8 participants (50%) achieving a clinically meaningful weight loss of ≥5%. 5. Safety — nausea (most frequent TEAE): Nausea was reported in 16.7% of participants in Part A (single ascending dose) and 21.4% in Part B (multiple dose), consistent with GLP-1 receptor agonist mechanism-of-action and dose-dependent in nature. 6. Additional treatment-related TEAEs: 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%) were reported; the overall safety and tolerability profile was considered acceptable across all cohorts.
Practice implications
Although TE-8105 remains investigational, its ~120-hour half-life supporting a Q2W subcutaneous dosing schedule represents a potential adherence advantage over current weekly GLP-1 receptor agonists for overweight or obese patients without type 2 diabetes — a distinction clinicians should monitor as phase II/III efficacy data emerge. The titration dosing strategy (initiating at 1.5 mg Q2W with stepwise escalation to 3.0 mg Q2W) appears to drive meaningful drug exposure and early weight loss signals (≥5% in 50% of titration-cohort participants), suggesting that gradual up-titration will likely be essential to mitigate GI adverse effects while optimizing therapeutic benefit. Clinicians should counsel patients that GI tolerability (nausea, vomiting, constipation, abdominal pain) remains the primary dose-limiting concern consistent with the GLP-1 receptor agonist class, and that close early monitoring during titration will be warranted in future clinical use.