2644-P: A Phase 3 Clinical Protocol Evaluating the Safety and Efficacy of NA-931 Alone and in Combination with Oral Semaglutide for the Treatment of Obesity

Introduction and Objective: NA-931 is a first-in-class, orally administered small-molecule quadruple receptor agonist targeting IGF-1, GLP-1, GIP, and glucagon receptors, developed for the treatment of obesity and type 2 diabetes. This Phase 3 study evaluates the safety and efficacy of NA-931 as monotherapy and in combination with oral semaglutide for the treatment of obesity. Methods: The combination of NA-931 with oral semaglutide is supported by complementary and potentially synergistic mechanisms regulating appetite, energy expenditure, insulin sensitivity, and body composition. BIOCOMBO-1 is a 68-week, randomized, double-blind, placebo-controlled global Phase 3 study enrolling 366 non-diabetic adults with overweight or obesity (BMI ≥30 kg/m², or ≥27 kg/m² with ≥1 obesity-related comorbidity). Participants are randomized to receive oral NA-931 120 mg once daily, NA-931 120 mg plus oral semaglutide 25 mg once daily, or placebo. The coprimary endpoints at Week 48 are percent change in body weight from baseline and the proportion of participants achieving ≥5% weight loss. Key secondary endpoints include ≥10%, ≥15%, and ≥20% weight loss, changes in BMI and waist circumference, and change in IWQOL-Lite-CT Physical Function score. Results: Topline results will be reported at a later date. It is anticipated that combining the quadruple receptor agonist NA-931 with oral semaglutide will result in more durable weight loss with preservation of lean mass compared with GLP-1 receptor agonist monotherapy. Conclusion: This ongoing study represents one of the earliest clinical evaluations of a rational, multi-pathway combination therapy in obesity. By simultaneously targeting appetite regulation, peripheral energy metabolism, and IGF-1-mediated lean mass preservation, this approach supports a unified neuro-metabolic framework and may advance obesity treatment beyond single-pathway pharmacotherapy toward integrated, mechanism-based strategies. Disclosure L. Tran: None.