1319-OR: Oral TIX100 Protects against Weight Rebound after Semaglutide Discontinuation

Introduction and Objective: Glucagon-like peptide 1 (GLP1) receptor agonists such as semaglutide have made medical weight loss possible, but for many the continued treatment necessary to maintain the weight loss is not sustainable. Reasons include gastrointestinal side effects, loss of lean/muscle mass, need for injections, and high cost. This results in half of the people stopping the medication within one year, which in most cases results in the regaining of the weight. Thus, there is an unmet need for non-GLP1 based, oral approaches to prevent this weight rebound that are affordable, well tolerated and do not impair muscle mass. The oral thioredoxin-interacting protein (TXNIP) inhibitor, TIX100, has recently been approved as an investigational new drug for diabetes by the FDA and found to be safe and well tolerated in a human Phase 1 trial. Interestingly, we recently discovered that TIX100 also has beneficial effects on weight control in mice. The goal of the current studies was therefore to determine whether TIX100 can prevent post-GLP1 weight regain. Methods: C57BL/6J male mice were rendered obese by high-fat diet (HFD), followed by 2 weeks of subcutaneous semaglutide treatment and weight and body composition, by quantitative magnetic resonance (QMR), were assessed 4 weeks after semaglutide discontinuation with or without oral TIX100 treatment. Results: HFD resulted in marked obesity and semaglutide led to a significant >6g weight loss; however, 4 weeks after semaglutide discontinuation untreated mice had regained almost 8g back, whereas mice receiving oral TIX100 maintained their weight loss despite ongoing HFD. QMR further showed that this difference was due to reduced fat mass as lean mass was preserved during TIX100 treatment. Conclusion: TIX100 may represent an attractive novel, oral, muscle-sparing, non-GLP1 approach for weight maintenance after GLP1-induced weight loss, in addition to its promising antidiabetic properties. Disclosure S. Jo: None. J. Chen: None. G. Jing: None. A. Shalev: Other - Co-founder, CSO/CMO; Current; TIXiMED, Inc.