A novel dual endothelin receptor antagonist (ERA), Macitentan, (manufactured by Actelion pharmaceuticals) had been approved for use against Pulmonary Arterial Hypertension (PAH) by the US FDA in October 2013. This came shortly after Actelion Pharma presented the results of its landmark clinical trial SERAPHIN (Study with Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) during an oral presentation at the European Respiratory Society Annual Congress 2013, held in Barcelona, Spain. Professor Hossein-Ardescir Ghofrani of the University Hospital Giessen, Giessen, Germany, had presented the results which highlighted the drug’s efficacy in terms of morbidity and mortality.
According to a study published online in the New England Journal of Medicine, SERAPHIN, led by Dr. Tomás Pulido of the Ignacio Chávez National Heart Institute, Mexico City, Mexico, proved that Macitentan significantly reduced morbidity and mortality resulting from PAH by 45%, and also reduced risk of PAH-related deaths by 50%.
Macitentan is a dual ERA. Endothelin receptors are evenly distributed on the surface of arterial smooth muscles and are specific to endothelin secreted by the endothelial cells. On secretion of the cells, these receptors are activated and cause a rise in the calcium levels in blood which in turn causes vasoconstriction. This is the pathogenesis for PAH. Macitentan has the potential to block these receptors and prevent constriction of blood vessels.
SERAPHIN focused on three subgroups, with 250, 250, and 242 volunteers in each group, all of them characterized as PAH patients after a right heart catheterization had been performed. They were treated with a placebo, a 3mg/day dosage and a 10mg/day dosage of Macitentan, respectively. Both phases of trials fared equally well in terms of meeting end-points (reducing / preventing adverse effects), with the 10mg/day dosage proving to be slightly more effective. Also, both phases saw same side-effects, with the worse case being peripheral edema.
SERAPHIN was considered to be more effective than other PAH drugs in more ways than one. First, it was the longest running trial, observed for 2 years. Second, it was the only trial to have focused on morbidity and mortality as its end-points. The other classes of drugs, including phosphodiesterase 5 inhibitors and prostacyanins, have only focused on reduction in pulmonary arterial pressure as their end points. Third, the patients participating in this study were allowed to continue with any non ERA, oral, concomitant medication aimed at lowering PAH, and yet its combination with Macitentan did not affect the results negatively.
According to Dr. Pulido, “This is one of the strengths of the study,” according to Pulido. “We showed that the benefit in the primary end point was the same with [PAH-drug-therapy]-naive patients as with patients treated with combination therapy.”
Ever since its approval by the FDA, Macitentan has been prescribed for the effective treatment of PAH in patients.