Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) with 
sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd. 
In October 2013, oral macitentan 10 mg once daily received its first global 
approval in the US, followed closely by Canada, for the treatment of pulmonary 
arterial hypertension (PAH). The drug has also received a positive opinion in 
the EU from the Committee for Medicinal Products for Human Use for the treatment 
of PAH, and is under regulatory review in several other countries for the same 
indication. Endothelin (ET)-1 influences pathological changes via two ET 
receptor subtypes (ETA and ETB), to which it binds with high affinity. ET-1 is 
implicated in several forms of vascular disease making it a valid target for the 
treatment of pulmonary vascular diseases such as PAH. Clinical development is 
underway for other indications, including Eisenmenger syndrome, ischaemic 
digital ulcers secondary to systemic sclerosis, and glioblastoma. Macitentan was 
also evaluated in idiopathic pulmonary fibrosis; however, a phase 2 trial did 
not meet its primary endpoint and further investigation in this indication was 
discontinued. Macitentan was developed by modifying the structure of bosentan in 
the search for an optimal dual ERA with improved efficacy and tolerability 
compared with other ERAs. This article summarizes the milestones in the 
development of macitentan leading to this first approval for PAH.