What question did this study set out to answer?

This research aims to identify a novel GLP-1 receptor agonist that promotes weight loss while preserving muscle mass.

June 7, 2026

2574-P: Discovery of RV-8451, a Novel, Oral, Muscle-Preserving Small Molecule GLP-1 Receptor Agonist

Key Points

This research aims to identify a novel GLP-1 receptor agonist that promotes weight loss while preserving muscle mass.
Characterized the GLP1R pharmacological profile using various assays.
Evaluated food intake and weight loss efficacy in diet-induced obese mice over 14 days.
Measured body composition and respiratory exchange ratio using EchoMRI and indirect calorimetry.
RV-8451 showed significant weight loss of up to 11% vs vehicle and fat mass reduction of up to 34% without loss of lean mass.
Post-treatment, cumulative body weight reduction reached 24% compared to vehicle, coupled with a 67% reduction in fat mass.
High-dose RV-8451 lowered respiratory exchange ratio, suggesting enhanced fat oxidation.

Abstract

Introduction and Objective: Peptide GLP1R agonists (GLP1RAs) are effective treatments for obesity, but have limitations, including tolerability and loss of lean mass. There is a need for next-generation GLP1RAs that promote weight loss while preserving muscle and improving metabolic health. This research describes the discovery of RV-8451, a first-in-class, oral, non-peptide GLP1RA in preclinical development, its in vitro and in vivo pharmacology, and its effect on muscle preservation. Methods: We characterized the GLP1R pharmacological profile using competition-binding, cAMP accumulation, and β-arrestin2 recruitment assays. Food intake and weight loss (WL) efficacy were evaluated in male diet-induced obese (DIO) humanized GLP1R mice treated with RV-8451 for 14 days, with body composition quantified by EchoMRI. Respiratory Exchange Ratio (RER) was measured by indirect calorimetry. Results: RV-8451 specifically binds to hGLP1R in vitro and produces robust activation of the Gαs-cAMP pathway without measurable β-arrestin2 recruitment, consistent with a fully G-protein biased agonist profile. In DIO hGLP1R mice, RV-8451 reduced food intake without altering water intake. After 14 days, RV-8451 produced marked WL (up to 11% vs vehicle) and fat mass reduction (up to 34%), with no change in lean mass. Post-treatment, WL continued for 7 days, then was sustained for 7 additional days, resulting in a cumulative 24% (vs vehicle) reduction in body weight and 67% reduction in fat mass, without loss of lean mass. In hGLP1R mice, high-dose RV-8451 lowered RER over 4 days, suggesting a shift toward greater fat oxidation. Conclusion: RV-8451 is the first muscle-preserving, non-peptide GLP1RA that delivers weight and fat mass loss while maintaining lean mass in preclinical obesity models. By reducing RER, RV-8451 may counteract metabolic adaptation and improve efficacy relative to current non-peptide GLP1RAs. Disclosure S. Collado: Employee; Current; Rivus Pharmaceuticals. H. Chobanian: None. M. Luse: None. B. Dalesandro: None. T.E. Richardson: None. A. Scott: None. C.A. Hamilton: None. S. Eaton: None. A. Cole: None. O.M. Khan: None. J. Dennis: Employee; Current; Rivus Pharmaceuticals. Stock/Shareholder; Current; Viking Therapeutics. A. Viacava Follis: Employee; Current; Rivus Pharmaceuticals. Employee; Ended; ROME Therapeutics. S.M. Khan: Employee; Current; Rivus Pharmaceuticals.

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