Macitentan: the evolution of the class endothelin receptor antagonists to improve efficacy and safety of PAH treatment

Pulmonary arterial hypertension (PAH) is a severe progressive disease, characterized by advanced remodeling of small pulmonary arteries and arterioles, which ultimately leads to right heart failure and death. Due to discovery of PAH pathophysiological targets, new medications have been developed and implemented into clinical practice. These medications compensate the deficiencies of endogenous prostacyclin and nitric oxide and also block the effects of endothelin-1 (ET-1). The role of the latter in PAH pathophysiology is related to its strong vasoconstrictory properties, as well as to a number of effects responsible for arterial wall remodeling. Clinical use of endothelin receptor antagonists (ERA) started in 2001, with the first agent of the class, bosentan, whose efficacy was demonstrated in a number randomized controlled trials. Macitentan is a novel potent double action oral ERA, developed with the purpose to improve efficacy and safety of PAH treatment through its tissue specificity. The new molecule blocks endothelin receptors type A and B and possesses improved physicochemical properties allowing for improved tissue penetration. Macitentan prevents an increase in pulmonary arterial pressure, right ventricle hypertrophy and improves survival in animal models. The SERAPHIN Study evaluated the effects of macitentan on morbidity/mortality in 742 PAH patients, randomized to macitentan 3 mg or 10 mg daily or placebo. Macitentan 3 mg and 10 mg daily was shown to reduce morbidity and mortality by 30% and 45%, respectively. By 6 month of the follow-up, there was an improvement in 6-minute walking test by + 16.8 m for macitentan 3 mg and +22.0 m for macitentan 10 mg daily. An improvement of the functional class, compared to baseline, was observed by 6 mo in 13% of placebo patients, 20% of macitentan 3 mg daily patients (p=0.04) and in 22% of 10 mg daily patients (0.006). Compared to placebo, macitentan significantly reduced pulmonary vascular resistance and improved cardiac index. It demonstrated a favorable safety profile. US Food and Drug Administration (FDA) approved macitentan (OPSUMIT) 10 mg once daily for the treatment of pulmonary arterial hypertension to delay disease progression.