Oral GLP-1RA TERN-601 for Adults With Obesity/Overweight: Placebo-Controlled, Multiple-Ascending-Dose, Phase 1 and 2 Studies.

Abstract

The safety, tolerability, pharmacokinetics, and efficacy of TERN-601, a once-daily, oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, were studied in Phase 1 and 2 clinical studies. The Phase 1 (28-day) and Phase 2 (12-week), randomized, double-blind, placebo-controlled, multiple-ascending-dose studies evaluated the safety, tolerability, pharmacokinetics, and efficacy (change in weight, appetite, and gastric emptying) of TERN-601 for adults with obesity or overweight. In the Phase 1 study, TERN-601 produced dose-dependent weight loss over 28 days, with statistically significant reductions versus placebo at all doses. Treatment was associated with GLP-1-consistent pharmacodynamic effects, including reduced appetite and delayed gastric emptying. In the Phase 2 study, TERN-601 doses ≥ 500 mg resulted in significantly greater mean percentage weight loss at Week 12 versus placebo. Gastrointestinal treatment-emergent adverse events were consistent with the GLP-1 receptor agonist class and dose-related. Three participants in the Phase 2 study experienced transaminase elevations consistent with potential drug-induced liver injury. TERN-601 demonstrated modest, dose-dependent weight loss with a gastrointestinal tolerability profile consistent with GLP-1 receptor agonists. However, liver safety findings observed in the Phase 2 study led to clinical development discontinuation. These data contribute to the overall understanding of oral small-molecule GLP-1 receptor agonists in obesity. ClinicalTrials.gov identifier: NCT06854952.