OR22-06 JUV-112: A Novel Biologic for Sustaining Weight Loss and Enhancing Metabolism through Energy Expenditure

Abstract Disclosure: R. Datta: None. V. Karuppagounder: None. A. Koranne: None. H. Kim: None. S. Louie: None. A. Yang: None. T. Mai: None. M. Chung: None. R. Jadhav: None. S. Tang: None. F. Liu: None. P. Handa: None. H. Yousef: None. J.D. O'Connell: None. Obesity and metabolic disorders are major global health challenges. While drugs targeting GIPR/GLP1R are potent in managing obesity by reducing appetite, there remains a pressing need for alternative therapies owing to their side effects. At Juvena, we have developed a biologics-based drug discovery platform that led to the identification of JUV-112, a promising candidate for treating obesity-related metabolic conditions. In vitro studies using differentiated 3T3-L1 adipocyte cells revealed that JUV-112 significantly reduced cellular lipid content by 66% (p<0.001), primarily through a seven-fold increase in lipolysis. In vivo studies further demonstrated that chronic administration of JUV-112 to high-fat diet-fed mice resulted in an 11% reduction in body weight compared to vehicle-treated animals (p<0.001), along with improved body composition, including an 15.58% decrease in fat mass and a 3.5% increase in the proportion of lean mass. Additionally, JUV-112 enhanced oral glucose tolerance (p<0.01), lowered serum insulin levels (p<0.01), and improved fasting blood glucose levels (138 mg/dl versus 182.5 mg/dl in the vehicle group, p<0.0001), suggesting improved insulin sensitivity. JUV-112 also significantly reduced intrahepatic lipid accumulation (p<0.001) and liver weight by 22.25% (p<0.05), compared to controls. Furthermore, it alleviated adipocyte hypertrophy in subcutaneous adipose tissue, indicating healthier fat storage. Notably, JUV-112 did not suppress food intake or affect intestinal fat absorption, offering a novel mechanism for improving metabolic health from a biologic. To explore the mechanism of weight loss in vivo, we measured energy expenditure in mice over two weeks at thermoneutrality (28°C) using a comprehensive Lab Animal Monitoring System (CLAMS). JUV-112 treatment significantly increased ANCOVA-adjusted energy expenditure in mice, supporting its role in boosting metabolic activity. We validated our finding in vitro by Seahorse assay in differentiated 3T3-L1 adipocytes. We demonstrated increased basal respiration and oxygen consumption in cells treated with JUV-112, indicating a direct effect on mitochondrial energy expenditure. One of the most significant challenges in weight loss therapies is preventing weight regain, which often occurs due to a decrease in resting metabolic rate. Our findings show that JUV-112, when administered after Semaglutide-induced weight loss in mice, effectively helped sustain body weight over a 6-week period. This ability to maintain weight, potentially driven by the sustained increase in energy expenditure, highlights JUV-112's potential as a novel approach for long-term weight management. Given its metabolic effects, JUV-112 may be an ideal candidate for combination therapies, potentially working with GIPR/GLP1R agonists to enhance overall metabolic health and prevent weight regain. Presentation: Sunday, July 13, 2025