Debra L. Beck and Eugene Braunwald, MD 

Pulmonary arterial hypertension (PAH) is a rare and progressive disorder characterized by pulmonary vascular remodeling resulting in high pulmonary artery pressure, cellular proliferation, and poor long-term outcomes. Mutations that lead to dysfunctional bone morphogenetic protein pathway signaling has been linked to both the hereditary and idiopathic subtypes. Sotatercept is a novel, first-in-class fusion protein, binds activins and growth differentiation factors in an attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. 

A total of 106 adults receiving background therapy for PAH were randomly assigned to 24 weeks of subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo.  

For the primary endpoint—the change from baseline to week 24 in pulmonary vascular resistance—the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group was -145.8 dyn · sec · cm-5 (p=0.003). For the 0.7-mg arm, the least-squares mean difference was -239.5 dyn · sec · cm-5 (p<0.001). This change was driven by a decreased mean pulmonary artery pressure (least-squares mean difference of -8.3 mm Hg and -13.4 mm Hg, respectively, between 0.3-mg and 0.7-mg vs. placebo). 

At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg and 0.7-mg groups compared to placebo for the change from baseline in 6-minute walk distance was 29.4 meters and 21.4 meters, respectively. 

Patients treated with sotatercept also showed a decrease in N-terminal pro-B-type natriuretic peptide levels, but there were minimal changes seen in any group in pulmonary wedge artery pressure and cardiac output.  

Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the higher-dose sotatercept group died from cardiac arrest during the trial. 

Summary 

The investigators concluded that treatment with sotatercept reduced pulmonary vascular resistance in patients receiving background therapy for PAH. Limitations of the study include its small sample size and short duration. Also, the trial was not powered for clinical outcomes. Additional trials of this agent are ongoing or planned.  

Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine remains the most trusted reference in the field and the leading source of reliable cardiology information for practitioners and trainees worldwide. Written and edited by global experts in the field, this award-winning text is an unparalleled multimedia reference for every aspect of this complex and fast-changing area. Dr. Braunwald also curates the extensive, bimonthly online updates that include “Hot Off the Press,” “Practice Updates,” and “Late-Breaking Clinical Trials.”

Preorder Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 12th Edition here! Publishing November 2021.