Development of FBL-140, a Best-in-Class, Once-Monthly Subcutaneous ActR2A/B Antagonist Antibody for Obesity and Related Comorbidities

Introduction and Objective: Recent data from the BELIEVE and COURAGE trials validate activin type II receptor (ActR2) pathway inhibition for high-quality weight loss (fat reduction with lean mass gain). Ligand blocking monotherapy in COURAGE showed submaximal efficacy, with worsening AEs in combination. Bimagrumab in BELIEVE was not optimized for convenient, subcutaneous (s.c.) dosing, and low affinity for ActR2A limits fat mass efficacy at lower doses. These limitations underscore the need for fully optimized molecules that comprehensively and conveniently inhibit the ActR2 pathway for obesity. Methods: We leveraged our machine-learning platform for multi-parameter optimization to design ActR2A/B antagonists. The pharmacokinetic (PK) and pharmacodynamic profile was characterized in mice and non-human primates (NHP). Efficacy was evaluated in B6 lean mice and DIO mice in combination with semaglutide. Manufacturability was assessed under stressed conditions. Results: FBL-140 has balanced, high-affinity binding to both ActR2A and ActR2B, resulting in greater potency vs bimagrumab in human primary skeletal muscle cells and adipocytes. Superior thermostability, reduced self-interaction and lower polyreactivity deliver best-in-class drug properties. Stress tests and high concentration studies demonstrate compatibility with s.c. dosing and long shelf-life. FBL-140 increased lean mass in B6 mice and achieved desired lean mass gain and fat mass loss in DIO mice in combination with semaglutide. Linear clearance and high exposure are observed over 4 weeks in NHP, with high bioavailability, and TMDD is overcome at a lower dose than known competitors. Conclusion: FBL-140 demonstrates a class-leading PK and manufacturability profile achieving full target engagement and efficacy, with modeling and simulation predicting once-monthly, low-volume s.c. injection in humans. Disclosure: S. He: None. W. Zhang: None. D. Tomar: None. O. Quintero-Monzon: None. V. Voynov: None. D. Redka: None. K. Trainor: None. C. Oborski: None. P.M. Kim: None. G. MacKay: None. R. Wideman: None. D.J. Baker: Employee; Ended; AstraZeneca. Stock/Shareholder; Current; AstraZeneca. V.D. Sood: None.