Development of macitentan for the treatment of pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a serious, chronic condition that, without early recognition and treatment, leads to progressive right heart failure and death. The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles compared with previous compounds. Macitentan's efficacy was demonstrated in an event-driven morbidity and mortality study of treatment-naive and background PAH therapy-treated 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-related hospitalizations and mortality and improved WHO FC and exercise capacity (6-min walk distance). Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. To date, this was the largest and longest prospective trial for PAH. Macitentan, currently the only approved oral PAH treatment shown to be safe and effective in delaying long-term progression and reducing PAH-related hospitalizations, has changed treatment paradigms from goal-directed to long-term outcome-oriented therapy.
Actelion Pharmaceuticals, US, Inc, South San Francisco, California.
Mona
M
Selej
Actelion Pharmaceuticals, US, Inc, South San Francisco, California.
Alain J
AJ
Romero
Pulmonary and Critical Care, Massachusetts General Hospital, Boston, Massachusetts.
Richard N
RN
Channick
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Martine
M
Clozel
D055808:Drug Discovery; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D065627:Familial Primary Pulmonary Hypertension / Q000188:drug therapy*; D006801:Humans; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan
SERAPHIN; drug development; endothelin; macitentan; pulmonary arterial hypertension