Preclinical and First-In-Human Evaluation of Ribupatide (HRS9531), a Dual GLP-1/GIP Receptor Agonist.
Ribupatide showed a favorable safety profile and significant weight loss in a small Phase 1 trial, but further studies are needed to confirm these effects in larger populations.
Where it sits
this study against the rest of the ribupatide corpusSummary and findings
This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of ribupatide (HRS9531) in preclinical models and a Phase 1 trial. The Phase 1 study involved 90 healthy Chinese participants receiving doses of ribupatide ranging from 0.1 to 8.1 mg. Results indicated a favorable safety profile and weight change in ribupatide groups compared to placebo.
Abstract
<h4>Aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>ClinicalTrials.gov identifier: NCT05152277.
Background
This study addresses the pharmacological profile of ribupatide, a dual GLP-1/GIP receptor agonist, which may have implications for managing conditions like type 2 diabetes and obesity. Prior knowledge indicated that GLP-1 and GIP receptor agonists can influence glucose metabolism and weight. The significance of this study lies in its exploration of ribupatide's safety and efficacy in human subjects following promising preclinical results.
Methods
The study included preclinical assessments in Sprague-Dawley rats, cynomolgus monkeys, and diet-induced obese mice, focusing on pharmacokinetics and pharmacodynamics. The Phase 1 clinical trial utilized a single-ascending dose (SAD) and multiple-ascending dose (MAD) design with 90 healthy participants receiving doses of ribupatide ranging from 0.1 to 8.1 mg. The primary endpoints were safety and tolerability, with treatment administered subcutaneously once weekly for 4 weeks.
Results
The primary endpoint indicated that ribupatide was well tolerated across all dose levels, with all treatment-emergent adverse events being mild-to-moderate in severity. After four weekly doses, the mean weight change in ribupatide groups ranged from -4.3 kg (-6.7%) to -7.7 kg (-9.6%), compared to -1.2 kg (-1.4%) in the placebo group. Fasting plasma glucose levels decreased in a dose-dependent manner following both single and multiple doses.
Interpretation
The findings suggest that ribupatide may have a favorable safety profile and potential efficacy in weight loss and glucose control, though the clinical significance of the weight changes should be interpreted cautiously. The study's small sample size and the fact that it was conducted in a single population may limit the applicability of the results. Further studies are needed to confirm these findings and assess long-term effects.
Key findings
- Mean weight change in ribupatide groups ranged from -4.3 kg (-6.7%) to -7.7 kg (-9.6%) after four weekly doses, compared with -1.2 kg (-1.4%) in the placebo group.
- Fasting plasma glucose decreased dose-dependently after single and multiple dosing.
- In the MAD, the mean half-life was 7-8 days across the dose range.
- A total of 90 healthy Chinese participants were randomised and received study treatment, of whom 87 (96.7%) completed the study.
- All treatment-emergent adverse events (TEAEs) were mild-to-moderate in severity, with no serious TEAEs or deaths reported.
Limitations
- Small sample size of 90 participants.
- Single population group (healthy Chinese participants).
- Short follow-up duration of 4 weeks.
- No long-term efficacy data reported.