Opsumit® (macitentan) is a novel dual endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process with the target of developing an ERA to address efficacy and safety Opsumit is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6 minute walk distance, worsened PAH symptoms and need for additional PAH treatment). Opsumit also reduced hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were treated with Opsumit® monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).
Current status in PAH
In April 2012, Actelion announced that the pivotal Phase III SERAPHIN outcome study met its primary endpoint.
Approval of the new drug application for Opsumit® (macitentan) was issued by the US Food and Drug Administration (FDA) on 18 October 2013 for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened PAH symptoms and need for additional PAH treatment).The need for PAH hospitalization was also reduced. In November 2013 Opsumit was subsequently approved in Canada.
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for Opsumit® (macitentan) in the treatment of pulmonary arterial hypertension on 24 October 2013. The CHMP recommended that the European Commission approves Opsumit®, as monotherapy or in combination, for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class II to III. Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease. The European Commission is expected to issue a final decision in two months.
Regulatory reviews are ongoing in Switzerland, Australia, Taiwan, Korea and Mexico.
The SERAPHIN study
SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve clinical outcome) was the largest and longest randomized, controlled study in PAH patients to include a clearly defined morbidity/mortality primary endpoint. The pivotal Phase III study was designed to evaluate the efficacy and safety of Opsumit® (macitentan) - a novel dual endothelin receptor antagonist that resulted from a tailored drug discovery process - through the primary endpoint of time to first morbidity and all-cause mortality event in patients with symptomatic PAH.
Global enrollment was completed in December 2009 with a total of 742 patients. Patients were randomized 1:1:1 to receive two different doses of macitentan (3 mg and 10 mg once daily) or placebo. Patients were allowed to receive PAH background therapy throughout the study, either PDE-5 inhibitors or oral/inhaled prostanoids. This event driven study was conducted in 151 centers from almost 40 countries in North America, Latin America, Europe, Asia- Pacific and Africa and was completed in the first half of 2012, with 287 patients having an adjudicated event.
Patients were randomized to placebo (n=250), macitentan 3 mg (n=250), or macitentan 10 mg (n=242). The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for macitentan 3 mg versus placebo was 0.70 (97.5% CI, 0.52 to 0.96; p=0.0108) and the hazard ratio for macitentan 10 mg versus placebo was 0.55 (97.5% CI, 0.39 to 0.76; p<0.0001). Worsening of pulmonary arterial hypertension was the most frequent primary end point event. The effect of macitentan on this end point was observed irrespective of background therapy for pulmonary arterial hypertension.
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.
Safety and Tolerability in SERAPHIN
Opsumit is contraindicated in pregnancy because it may harm the developing fetus. Females of reproductive potential should be counselled on the use of reliable contraception and have a negative pregnancy test prior to initiating therapy and monthly thereafter.
Other ERAs have been associated with elevations of aminotransferases, hepatotoxicity, and liver failure. Liver enzyme tests should be obtained prior to initiation of Opsumit® and repeated during treatment as clinically indicated. If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by clinical symptoms of hepatoxicity, discontinue Opsumit®. Decreases in hemoglobin concentration and hematocrit occurred following administration of other ERAs and were observed in clinical studies with OPSUMIT. The decreases occurred early and stabilized thereafter. Decreases in hemoglobin seldom require transfusion. Initiation of Opsumit® is not recommended in patients with severe anemia. Hemoglobin should be measured prior to initiation of treatment and repeat during treatment as clinically indicated.
Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue Opsumit®.
Other ERAs have been associated with adverse effects on spermatogenesis. Men should be counseled about potential effects on fertility.
The use of Opsumit® with strong CYP3A4 inducers or inhibitors should be avoided.
The most common adverse reactions (more frequent than placebo by ≥3%) observed in patients treated with Opsumit were anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection.
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.