2561-P: RV-202, a Novel Oral Mitochondrial Uncoupler, Drives Durable, Fat-Selective Weight Loss in Mouse Model of Obesity

Introduction and Objective: RV-202 is a novel oral mitochondrial uncoupler (MU) in development for the treatment of obesity and associated comorbidities. The objective of this preclinical research was to characterize the in vitro activity and mechanism of action of RV-202 and to demonstrate its ability to increase energy expenditure (EE) and fat oxidation and induce weight loss (WL) in a mouse model of obesity. Methods: In vitro uncoupling activity and potency were assessed by oxygen consumption rate (OCR) in cells using Seahorse XF analyzers. In vivo, EE and respiratory exchange ratio were measured by indirect calorimetry in male C57BL/6 wildtype mice housed at thermoneutrality after 3 days of vehicle or RV-202 at 3 doses. WL efficacy was evaluated in male diet-induced obese (DIO) mice treated with RV-202 for 14 days at thermoneutrality, with body composition quantified by EchoMRI. Results: RV-202 increased OCR in HepG2 cells and C2C12 myoblasts with EC50 values of 2.5 µM and 2.6 µM respectively, mostly via adenine nucleotide translocase. OCR increases were predominantly fatty acid oxidation (FAO) dependent (% FAO = 56.6 ± 6.3), consistent with MU. In WT mice, RV-202 increased EE and fat oxidation in a dose-dependent manner (up to 26% and 58%, respectively) over 3 days, without elevating body temperature. In DIO mice, RV-202 similarly increased EE and fat oxidation, resulting in significant WL (up to 16%) and fat mass reduction (up to 81%) after 14 days of once-daily oral administration, with no significant effect on lean mass. The WL effect was sustained for 7 days after treatment cessation. Conclusion: RV-202 is an oral MU that increases FAO-dependent respiration in vitro. In vivo, RV-202 produces dose-dependent increases in EE and fat oxidation, leading to fat-selective, muscle-preserving WL in DIO mice. The sustained WL after washout indicates durable metabolic effects, supporting RV-202 as a promising treatment for obesity and associated cardiometabolic disease. Disclosure B. Dalesandro: None. H. Chobanian: None. T.E. Richardson: None. A. Scott: None. M. Luse: 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. S.M. Khan: Employee; Current; Rivus Pharmaceuticals. S. Collado: Employee; Current; Rivus Pharmaceuticals.