Safety, Pharmacokinetics and Pharmacodynamics of the GLP-1/GIP/GCG Receptor Agonist UBT251 Injection: A Randomized, Placebo-Controlled Phase 1a/1b Study.

AIMS: UBT251 is a novel triple agonist peptide targeting the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This first-in-human Phase 1a/1b study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of UBT251. MATERIALS AND METHODS: This randomized, double-blind, placebo-controlled study consisted of two clinical trials. The Phase 1a study was a single-ascending-dose trial, in which participants received a single subcutaneous injection of UBT251 at doses ranging from 0.1 to 4.5 mg. The Phase 1b study was a multiple-ascending-dose trial conducted in participants with overweight or obesity without diabetes. UBT251 was administered once weekly by subcutaneous injection for 12 consecutive weeks. Safety and tolerability were the primary endpoints. RESULTS: UBT251 was generally well tolerated, with laboratory investigations, decreased appetite and gastrointestinal adverse events being the most common adverse effects. In participants with overweight or obesity, once-weekly subcutaneous injections of UBT251 at doses of 1, 3 and 6 mg for 12 weeks led to a mean body weight reduction of 8.96-13.48 kg, compared with the 1.57 kg increase observed in the placebo group. Following single and multiple dosing, UBT251 exhibited approximately linear pharmacokinetics across the 1.0-6.0 mg dose range. UBT251 treatment also demonstrated favourable metabolic effects, including reductions in fasting plasma glucose, haemoglobin A1c and lipid parameters. CONCLUSIONS: UBT251 demonstrated an acceptable safety profile and predictable pharmacokinetic properties, accompanied by substantial weight reduction and meaningful metabolic improvements. These findings strongly support the continued clinical development of UBT251 as a potential therapeutic option for obesity and type 2 diabetes. TRIAL REGISTRATION: ChiCTR2600116148 and ChiCTR2600123803 (https://www.chictr.org.cn/).