All of our existing therapies for Pulmonary Arterial Hypertension act by vasodilation or relaxing blood vessels. The current medications fall into one of three basic classes:
1. PDE5 inhibitor
a. Sildenafil (Revatio/Viagra)
b. Tadalafil (Adcirca/Cialiis)
c. Riociguat (Adempas—not truly a PDE5inhibitor but similar action)
2. ERA
a. Ambrisentan (Letairis)
b. Bosentan (Tracleer)
c. Macitentan (Opsumit)
3. Prostanoid/Prostaglandin
a. Treprostinil (Remodulin/Tyvaso/Orenitram)
b. Epoprostenol (Flolan/Veletri)
c. Selexipag (Uptravi)
As we have learned more about PAH, our thinking has gradually shifted away from vasoconstriction (squeezing of blood vessels) as the primary abnormality in PAH. We have come to learn that the cells that make up the pulmonary arteries are responding to abnormal signals and this leads to increased cell size (hypertrophy) and cell proliferation. The driving force behind these abnormalities is probably an imbalance in the on and off switches that regulate cell growth.
Imagine if the traffic lights at an intersection malfunctioned and the green light was on the whole time. This would lead to big problems. In a similar way, the biology of blood vessels relies on a complex set of on and off signals to prevent excessive growth and to preserve responsiveness.
Sotatercept is a new molecule that is being studied in PAH. It works by changing the balance of on and off signals. Sotatercept is an engineered human fusion protein containing the extracellular domain of the human Activin receptor IIA. It binds to and inhibits activin and other members of the transforming growth factor -β (TGF-β) superfamily. This TGF- β superfamily is a major controller of cell growth and function.
Acceleron is starting their phase 2 study after exciting results in animal models of the PAH disease. The medication is administered as a shot under the skin (subcutaneous) every 3 weeks. The primary objective of the study is to see if the drug leads to reductions in pulmonary vascular resistance over a six-month period. Patients will have to have a right heart catheterization at entry and at six months.
This study marks an exciting development in the treatment of Pulmonary Arterial Hypertension. Stay tuned for more information. To get more information contact your PAH center of excellence.
