Abstract
The endothelin pathway is a key pathway for the pathogenesis of pulmonary arterial hypertension (PAH). Antagonism of this pathway is recommended as initial therapy in low-risk patient with PAH to inhibit fibrosis, cell proliferation, and inflammation caused by endothelin. Prior to October 2013, ambrisentan, a selective ETA receptor antagonist and bosentan, a dual ETA/ETB antagonist, were the only currently available agents for PAH targeting the endothelin pathway. Based on the results of the SERAPHIN trial, macitentan (brand name Opsumit®), a new ETA/ETB antagonist, has been US FDA approved to delay disease progression and reduce hospitalizations for PAH. SERAPHIN is the first ERA trial to use an event-driven strategy with a composite primary end point of morbidity or mortality. Previous trials have focused on short-term outcomes, such as improved 6-min walk distance and WHO functional class.
Financial & competing interests disclosure
RL Benza discloses honoraria for lectures from Actelion and United Therapeutics; has received grant support from Actelion, Bayer, GeNO, Ikaria, Gilead, Lung Rx, Novartis and United Therapeutics; is on steering committees for Actelion, Ikaria and Bayer and is on advisory boards for Bayer, Novartis, Gilead and United Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
Endothelin (ET) plays an important role in the pathophysiology of pulmonary arterial hypertension (PAH) causing vasoconstriction, proliferation and fibrosis in the pulmonary vasculature.
Macitentan, a new ETA/ETB receptor antagonist, has been approved by the US FDA to delay disease progression and reduce hospitalizations for PAH based on results of the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome trial.
The Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome study represents an important shift in clinical trial design, away from the emphasis of short-term PAH trials, which have mainly focused on improvements in exercise capacity and toward morbidity and mortality.
Safety considerations with macitentan include most notably risk of embryo-fetal toxicity and as such is only available to females through enrollment in a Risk Evaluation and Mitigation Strategies program. Other noted adverse effects include anemia, nasopharyngitis, bronchitis, headache, influenza and urinary tract infection.
Future treatment pathways targeting proliferation, immunosuppression and inflammation are currently under investigation.