Treatment of pulmonary arterial hypertension with the dual endothelin receptor antagonist macitentan: clinical evidence and experience

Abstract

Macitentan (10 mg once daily orally), a dual endothelin receptor antagonist (ERA) developed by modifying the structure of bosentan to increase the efficacity and safety, is approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal SERAPHIN trial, (a landmark trial in the history of PAH trials because of the large number of included patients, the long-term follow up and the first trial with morbidity/mortality as the primary endpoint) showed a reduction of the risk of a morbidity or mortality event by 45% over the treatment time compared with placebo. The positive effect on the primary endpoint was observed whether or not the patient was already on PAH therapy. There has been no direct comparison between macitentan and other ERAs, which were approved based on improved exercise capacity, but preclinical and clinical data suggest better pharmacological and safety profiles. Further analyses of the SERAPHIN trial investigated the predictive value of different indices and events on long-term outcome and mortality. The efficacy in children, the long-term effects and safety of macitentan and its place in combination therapy compared with other ERAs are still under investigation. This review presents the preclinical evidence of superiority of macitentan compared with other ERAs, and the available clinical trial data. The place of macitentan in the therapeutic algorithm for PAH treatment, post-marketing experience and future perspectives are discussed.

Comparative effectiveness of endothelin receptor antagonists on mortality in patients with pulmonary arterial hypertension in a US Medicare population: a retrospective database analysis

“…11,14 Currently available ERAs differ in their endothelin receptor specificity and binding properties, tissue penetration, and other pharmacologic characteristics, which theoretically could be associated with different outcomes. 15,16 However, survival was not assessed as a separate endpoint in the pivotal trials for the ERAs bosentan (Study 351 and BREATHE-1) and ambrisentan (ARIES-1 and -2). [17][18][19] The primary endpoint for all of these trials was a change in exercise capacity (6-min walk distance).…”

Orphan Drug Use in Patients With Rare Diseases: A Population-Based Cohort Study

“…Endothelin-1 is a key mediator of PAH, causing proliferation and vasoconstriction in pulmonary vascular smooth muscle cells, and proliferation and vasodilation in pulmonary endothelial cells ( Sitbon and Morrell, 2012 ). Macitentan, derived from the structure of bosentan, is generally well tolerated ( Keating, 2016 ; Belge and Delcroix, 2019 ) and was reported to significantly reduce morbidity and mortality ( Pulido et al, 2013 ; Kim et al, 2016 ). The most frequent adverse events associated to macitentan included anemia, nasopharyngitis, bronchitis and headache ( Belge and Delcroix, 2019 ), whereas adverse effects on liver function were observed for bosentan ( Keating, 2016 ; Kuang et al, 2018 ).…”

“…Macitentan, derived from the structure of bosentan, is generally well tolerated ( Keating, 2016 ; Belge and Delcroix, 2019 ) and was reported to significantly reduce morbidity and mortality ( Pulido et al, 2013 ; Kim et al, 2016 ). The most frequent adverse events associated to macitentan included anemia, nasopharyngitis, bronchitis and headache ( Belge and Delcroix, 2019 ), whereas adverse effects on liver function were observed for bosentan ( Keating, 2016 ; Kuang et al, 2018 ). Compared to other ERAs, macitentan has been shown ten times more potent than bosentan in lowering blood pressure ( Iglarz et al, 2008 ).…”

Treatment of pulmonary arterial hypertension in children

“…Macitentan is a dual endothelin receptor antagonist which has been approved for the treatment of PAH in adults, but is used off-label in children. Macitentan is able to penetrate deeper into the tissure and and also binds longer to the ETA receptor compared with bosentan (60). A single center prospective study in a cohort of 13 patients aged 12 to 35 years over 24-week showed a beneficial effect of a switch from bosentan to macitentan with respect to exercise capacity (61).…”