1. Macitentan, a derivative of the endothelin receptor antagonist bosentan, reduced morbidity from pulmonary arterial hypertension compared to placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Medical therapies for pulmonary arterial hypertension (PAH) generally work by reducing the pressure in the pulmonary vasculature. Endothelin receptor antagonists accomplish this by causing relaxation of the pulmonary vessels. Bosentan, licensed by Actelion Pharmaceuticals, is one of the main endothelin receptor antagonists on the market at present.
In this study (sponsored by Actelion), the bosentan derivative macitentan was compared to placebo for treatment of PAH. Macitentan was designed to be more efficacious and have a better safety profile than bosentan, but this study does not compare the two drugs directly.
Unlike other trials of PAH therapies which focus on exercise capacity as the primary end point, this trial used a composite endpoint of death and progression of PAH requiring additional treatment. Macitentan was found to reduce the risk of worsening PAH compared to placebo. A higher dose of macitentan was associated with a greater reduction in risk.
Relevant Reading: The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist
In-Depth [randomized controlled trial]: This trial, known as SERAPHIN, randomized 742 PAH patients into 3 groups: placebo, 3mg macitentan once daily, 10mg macitentan once daily. Patients with a variety of etiologies of PAH were enrolled, including idiopathic, heritable and drug-related etiologies. The most common PAH etiology in the study was “idiopathic” followed by “associated with connective-tissue disease”. The mean duration of treatment was approximately 96 weeks.
The primary end point was time from treatment to a PAH-related event, including initiation of further medical or surgical treatment, or death from any cause. However, the number of deaths was low and the trial was not powered to show an effect on mortality alone. As such, although macitentan reduced the rate of the composite endpoint, this was primarily driven by reducing the rate of PAH-related morbidity, not mortality. The hazard ratio of 3mg macitentan vs. placebo was 0.67 (97.5% CI, 0.46 to 0.97; P=0.01). The hazard ratio of 10mg macitentan vs. placebo was 0.50 (97.5% CI, 0.34 to 0.75; P<0.001).
Macitentan was associated with a similar incidence of adverse events as placebo, though nasopharyngitis, anemia and headaches were more common in the macitentan groups than the placebo group. Anemia has been reported in conjunction with other endothelin receptor antagonists.
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