The potential for macitentan, a new dual endothelin receptor antagonist, in the treatment of pulmonary arterial hypertension

Abstract

In recent years in the management of pulmonary arterial hypertension (PAH), endothelin receptor antagonists (ERAs) represent a well-established class of therapeutic agents with clear beneficial effects. Macitentan (Opsumit®), a dual ERA optimized for efficacy and safety, is the newest drug in the class. Macitentan presents a number of key beneficial characteristics, including increased in vivo preclinical efficacy versus existing ERAs, resulting from sustained receptor binding and physicochemical properties that allow enhanced tissue penetration. The clinical pharmacokinetics studies also indicated a low predilection of macitentan for drug–drug interactions. In the SERAPHIN trial, a phase III long-term study of PAH, macitentan significantly reduced morbidity and mortality by 45% versus placebo, providing sustained long-term improvements in exercise capacity. No association was found between changes in exercise capacity and long-term clinical outcomes, but improved cardiopulmonary hemodynamics were recorded in macitentan-treated patients irrespective of baseline background PAH therapy or World Health Organization functional class. Based on these favorable data, the US Food and Drug Administration approved the 10 mg/day dose in late 2013 and the same process has recently been concluded by the European Medicines Agency.