SUN-663 Preclinical Evaluation of SYNT-101: Effects on Glycemic Control, Weight Loss, and Body Composition in DIO Rodents

Abstract Disclosure: M. Hudson: Syntis Bio. L. Sandoval: Syntis Bio. S. Pizzo: Syntis Bio. C. Dial: Syntis Bio. D. Sim: Syntis Bio. P.D. Susilo: Syntis Bio. F. Seta: None. R. Sharma: None. M. Lanchantin: Syntis Bio. S. Zale: None. G. Traverso: Syntis Bio. R. Langer: Syntis Bio. R. Dhanda: Syntis Bio. V. Sethuraman: Syntis Bio. Background: SYNT-101 is a novel orally administered therapeutic designed to treat obesity and related metabolic disorders by replicating the metabolic effects of gastric bypass through precise tissue coating. Developed in porcine models, it has demonstrated targeted nutrient blocking; however, its effects have yet to be demonstrated for weight loss, body composition, and hormonal regulation. We performed a comprehensive investigation characterizing these parameters in rodent models of obesity. Methods: Sprague-Dawley rats (20 weeks old, n=16) were maintained on an ad libitum high-fat diet (HFD, ResearchDiets D12492) for 12 weeks prior to study initiation to promote acclimation and induce weight gain. On Study Day 0, rats were pair-stratified by weight and randomly assigned to either the treatment group (SYNT-101, n=6) or control group (vehicle, n=6). The treatment group received a daily oral gavage of SYNT-101 (2 mL/kg), while the control group received saline (2 mL/kg). Throughout the 6-week study, body weight and food consumption were monitored daily, and body composition changes, including lean and fat mass, were assessed using EchoMRI, with a focus on epididymal and mesenteric white adipose tissue (eWAT and mWAT). Plasma samples were collected at both the study initiation (Day 0) and completion (Day 42) to assess metabolic and satiety hormone profiles. At the study’s conclusion, all rats were euthanized, and gastrointestinal tissue was harvested for further analysis. Results: SYNT-101 demonstrated visual evidence of transient deposition in the duodenum and showed a significant reduction in glucose uptake during OGTT. Clearance was visually confirmed within 24 hours of administration. The 6-week study demonstrated 1% body weight reduction each week and an average 10% daily reduction in food intake. Importantly, the treatment preserved lean muscle mass, while achieving a 20+% reduction in fat mass, including reductions in eWAT and mWAT. Additionally, DIO rats demonstrated outstanding tolerability throughout the 6-week treatment period. Conclusions: SYNT-101 demonstrates promising effects on weight loss, glucose metabolism, and body composition in DIO rodent models. Most notably, the treatment shows consistent, weekly weight loss, significantly reduced adiposity, while effectively preserving lean muscle mass, a critical limitation to existing weight loss interventions. These findings highlight the therapeutic potential of SYNT-101 for managing obesity and related metabolic disorders. Presentation: Sunday, July 13, 2025