048: Population Modeling Analyses of Sotatercept Pharmacokinetics, Safety & Efficacy in Healthy Participants & Patients With Pulmonary Arterial Hypertension

Statement of Purpose: To describe Sotatercept pharmacokinetics (PK) after intravenous and subcutaneous (SC) administrations, and its influence on hemoglobin (Hgb, a safety endpoint), in adults, including healthy participants and patients with pulmonary arterial hypertension (PAH); and to characterize the relationships between Sotatercept exposures with efficacy endpoints 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR) and N-terminal pro-B natriuretic peptide (NT-proBNP) in patients with PAH.

Description of Methods & Materials: A population PK model was constructed using data from two Phase 1 studies in healthy participants, two Phase 2 studies and 1 Phase 3 study in patients with PAH. Data collected after placebo and Sotatercept dosing in these Phase 1/2/3 studies supported a model of Sotatercept effect on Hgb dynamics [1]. Measurements of 6MWD, PVR and NT-proBNP in PAH patients were used to develop separate exposure-response models using nonlinear mixed effect modeling. Covariate analyses were conducted to identify significant predictors of variability in PK and exposure-response relationships.

Data & Results: Sotatercept PK was characterized by a 2-compartment model with first order absorption for SC dosing and linear disposition. Body weight and albumin concentrations were significant predictors of PK. Sotatercept effects on Hgb dynamics were captured using a previously published semi-mechanistic model describing the Sotatercept driven stimulation of erythroid lineage [1]. 6MWD response was modeled as the sum of predicted baseline 6MWD, an Hgb-mediated effect, an Emax function of time, and a power function of Sotatercept average concentration (Cavg) at Week 24. Patients classified into World Health Organization (WHO) Class II were predicted to have a higher baseline 6MWD compared to patients in WHO Class III. Age was also associated with 6MWD. PVR decreased with increasing Sotatercept Cavg according to a power relationship. PAH disease duration, baseline PVR and prostacyclin infusion each influenced the effect of Sotatercept on PVR. The exposure-response model for time to NT-proBNP < 300 pg/mL was described with a Cox proportional hazards model including the effect of Sotatercept Cavg. Baseline WHO functional class was found to decrease the probability of an event for NT-proBNP < 300 pg/mL in both placebo and Sotatercept recipients.

Interpretation, Conclusion or Significance: All models adequately characterized the observed data. The predicted 6MWD and predicted probability of NT-proBNP < 300 pg/mL increased while the predicted PVR decreased with increasing Sotatercept exposures, approaching a plateau at the corresponding Cavg range of the clinical dose of 0.7 mg/kg SC every 3 weeks.

Disclosures: The authors declare that there is no conflict of interest.