Population Pharmacokinetic/Pharmacodynamic and Exposure-Response Modeling Analyses of Sotatercept in Healthy Participants and Patients with Pulmonary Arterial Hypertension.

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_avg) at week 24 is associated with increased predicted 6MWD, increased probability of NT-proBNP concentration < 300 pg/mL, decreased predicted PVR, and increased Hgb which was clinically manageable. All these responses approached their corresponding plateaus at a C_avg range associated with the dose of 0.7 mg/kg Q3W SC. Statistically relevant covariates included age and iron supplementation which slightly increased Hgb-mediated effect for 6MWD, PAH disease duration, and baseline therapy infusion with prostacyclin for PVR, and WHO functional class for NT-proBNP. The magnitudes of the impact of these covariates are not clinically meaningful. Taken together, these results support an appropriate benefit-risk profile for the FDA-approved target dose for sotatercept of 0.7 mg/kg Q3W SC.