Sotatercept is a breakthrough, first-in-class biologic, recently approved by the Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (PAH). Exposure-response (E-R) analyses and pharmacokinetic/pharmacodynamic (PK/PD) modeling were performed for sotatercept after intravenous and subcutaneous (SC) administrations. Clinical endpoints included 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), and probability of N-terminal pro-B natriuretic peptide (NT-proBNP) concentrations <
300 pg/mL for efficacy, and hemoglobin (Hgb) for safety from two Phase 1 studies, two Phase 2 studies, and one Phase 3 study. E-R models using nonlinear mixed effect modeling approach were developed for 6MWD and PVR, while Cox proportional hazards model and semi-mechanistic PK/PD model were used for NT-proBNP and Hgb. Covariate analyses were conducted to identify significant predictors of variability for each of these clinical endpoints. Modeling results showed that increasing sotatercept average concentration (C