Preclinical and First‐In‐Human Evaluation of Ribupatide ( HRS9531 ), a Dual GLP ‐1/ GIP Receptor Agonist

Abstract

ABSTRACT Aims This study assessed the preclinical and clinical pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of ribupatide (HRS9531), a novel dual agonist of glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors. Methods Preclinical assessments of ribupatide included in vitro functional receptor potency assays, PK evaluations in Sprague–Dawley (SD) rats and cynomolgus monkeys and PD assessments in diet‐induced obese (DIO) mice. The Phase 1 study comprised single‐ascending dose (SAD; 0.1, 0.3, 0.9, 2.7, 5.4 and 8.1 mg) and multiple‐ascending dose (MAD; 0.9, 2.7 and 5.4 mg [2.7/2.7/4.0/5.4 mg]) parts. In the MAD part, ribupatide or placebo was administered subcutaneously once weekly for 4 weeks. The primary endpoints were safety and tolerability. Results Ribupatide is a chemically synthesised polypeptide that activates both GLP‐1 and GIP receptor signalling pathways in vitro. In SD rats and cynomolgus monkeys, ribupatide demonstrated good subcutaneous bioavailability. In DIO mice, it significantly reduced body weight and cumulative food intake over 28 days compared with vehicle‐treated controls. These preclinical PK/PD findings provided a rationale for clinical studies. A total of 90 healthy Chinese participants were randomised and received study treatment, of whom 87 (96.7%) completed the study. Ribupatide was well tolerated across all dose levels, with all treatment‐emergent adverse events (TEAEs) being mild‐to‐moderate in severity and no serious TEAEs or deaths reported. In the MAD, the mean half‐life was 7–8 days across the dose range. Fasting plasma glucose decreased dose‐dependently after single and multiple dosing. After four weekly doses, mean weight change in ribupatide groups ranged from −4.3 kg (−6.7%) to −7.7 kg (−9.6%), compared with −1.2 kg (−1.4%) in the placebo group. Conclusions Ribupatide exhibited a favourable safety and tolerability profile, along with PK properties consistent with once‐weekly administration. Its glucose‐lowering and weight‐loss effects support further clinical development for the treatment of type 2 diabetes mellitus and obesity. Trial Registration: ClinicalTrials.gov identifier: NCT05152277.