Macitentan (Opsumit®) is an orally available endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process in Actelion’s laboratories, which is currently approved for the treatment of pulmonary arterial hypertension (PAH), a chronic, life-threatening disorder which severely compromises the function of the lungs and heart.
Current status in Eisenmenger syndrome
Macitentan is currently being studied in the Phase III study MAESTRO (MAcitentan in Eisenmenger Syndrome To RestOre exercise capacity). A multi-center, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to evaluate the effects of macitentan on exercise capacity in subjects with Eisenmenger Syndrome.
This study is ongoing with approximately 220 subjects to be randomized in a 1:1 ratio into 2 treatment groups (macitentan 10mg or placebo) over a 16 week treatment period.
Current Status in other indications
Following excellent preclinical results, a Phase I/Ib open-label study was initiated with macitentan in patients with recurring glioblastoma. Actelion will approach Health Authorities for further discussions about the future development of macitentan in new and recurring glioblastoma.
Available Clinical Data
Macitentan has been studied in SERAPHIN, a multicenter, double-blind, placebo-controlled, parallel-group, event-driven, Phase III outcome study in 742 patients with symptomatic PAH, who were randomized to three treatment groups (placebo [N = 250], 3 mg [N = 250] or 10 mg [N = 242] of macitentan once daily), to assess the long-term effect on morbidity or mortality.
Treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio [HR] 0.55; 97.5% CI: 0.39 to 0.76; logrank p < 0.0001) of the composite morbidity-mortality endpoint up to EOT when compared to placebo. The treatment effect was established early and was sustained. In patients already on background therapy for PAH treatment with macitentan 10mg resulted in a 38% risk reduction (HR 0.62; 97.5% CI: 0.43 to 0.8; logrank p=0.0094) of the composite morbidity-mortality endpoint compared to placebo.
The risk of PAH related death or hospitalization for PAH up to EOT was reduced by 50% (HR 0.50; 97.5% CI: 0.34 to 0.75; logrank p < 0.0001) in patients receiving macitentan 10 mg (50 events) compared to placebo.
Efficacy of macitentan 10 mg on the primary endpoint was consistent across subgroups of age, sex, ethnic origin, geographical region, aetiology, by monotherapy or in combination with another PAH therapy and by WHO FC (I/II and III/IV).
The most commonly reported adverse drug reactions are nasopharyngitis (14.0%), headache (13.6%) and anaemia (13.2%, see section 4.4). The majority of adverse reactions are mild to moderate in intensity.
2013 > US FDA approval of Opsumit 10mg tablets in PAH
2012 > SERAPHIN outcome study meets its primary endpoint
2007 > Initiation of Phase III SERAPHIN study in PAH patients
2005 > Initiation of Phase II dose ranging study
2004 > Entry-into-man
2003 > Selection of macitentan for initiation of preclinical studies
Key scientific literature
Pulido T et al. N Engl J Med 2013;369:809-18.
Iglarz M. et al. J Pharmacol Exp Ther. 2008;327(3):736-45.
Iglarz M et al. Am J Respir Crit Care Med 2011;183:A6445.
Sidharta PN et al. Eur J Clin Pharmacol 2011;67(10):977-84.
Bruderer S et al. E AAPS J 2011 Dec 22 [Epub ahead of print].
Bruderer S et al. Amer Coll of Clin Pharmacol 40thAnnual Meeting, Sep 11-13, 2011; Chicago, USA.