FBL-140, a Best-in-Class ActR2A/B mAb Designed for Infrequent SC Dosing for Treatment of Obesity

Introduction and Objective: The BELIEVE trial showed ActR2A/B antagonism drives weight loss and lean mass gain. Bimagrumab + semaglutide therapy induced 22% weight loss (93% from fat), but 30 mpk i.v. bimagrumab was required for full activity, associated with high Cmax and dose-related adverse effects. FBL-140 is a human mAb designed for exceptional manufacturability, PK and target engagement at low doses. We used PK analysis from NHP and simulation to show FBL-140 can achieve full activity in humans via convenient quarterly s.c. dosing. Methods: A 28-day, single dose PKPD study of FBL-140 in NHP at 3, 10 mpk i.v. and 10 mpk s.c. was conducted. Drug levels and PD were measured. Human PK parameters were estimated by a 2-compartment popPK model with parallel linear and saturable clearances from allometrically scaled NHP data. Human PK and dose were simulated using empirical and mechanistic models. Results: FBL-140 at 3 mpk i.v. had slow linear clearance, complete TMDD profile and significant exposure over 3 weeks, supporting accurate parameter modeling. 10 mpk mitigated TMDD impact and low linear clearance was observed over 28 days for i.v., while s.c. dosing showed minimal TMDD at day 28. popPK modeling showed very low linear clearance and 84% bioavailability. Activin A levels were high and sustained in 10mpk arms for 28 days, reducing over time in the 3 mpk i.v. arm, in line with exposure. LDL levels were stable and in normal range. Empirical modeling predicts FBL-140 has very long human half-life at pharmacologically relevant concentrations, sufficient for a low QM dose to maintain efficacious steady state concentrations; mechanistic modeling also predicts high target engagement through the dose period. With one lead-in s.c. dose, a Q3M schedule is achievable via s.c. injection, supported by early formulation studies. Conclusion: Quarterly s.c. dosing, enabled by FBL-140’s strong manufacturability and PK, offers a unique opportunity for lean mass preserving weight loss for patients with obesity. Disclosure: V.D. Sood: None. S. He: None. D.J. Baker: Employee; Ended; AstraZeneca. Stock/Shareholder; Current; AstraZeneca. R. Wideman: None. W. Zhang: None. V. Voynov: None. D. Tomar: None. O. Quintero-Monzon: None. D. Marcantonio: None. A. Endsley: Employee; Current; Certara, Inc.