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The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin\u2010axis blockade while improving adverse\u2010effect profiles compared with previous compounds. Macitentan's efficacy was demonstrated in an event\u2010driven morbidity and mortality study of treatment\u2010naive and background PAH therapy\u2013treated symptomatic patients. Compared to placebo, 10 mg of macitentan significantly reduced the relative risk of morbidity and mortality by 45%, primarily by delaying PAH worsening, most prominently in World Health Organization (WHO) functional class II and III PAH patients. Macitentan reduced the incidence of the composite end point of PAH\u2010related hospitalizations and mortality and improved WHO FC and exercise capacity (6\u2010min walk distance). Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. 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