ABOUT MACITENTAN

Macitentan is an orally available endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process in Actelion’s laboratories.

Macitentan (Opsumit®) 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. The product is commercially available in over 35 markets, including the US (since November 2013), Germany (since January 2014) and Japan (since June 2015). The registration process for other countries is ongoing.

CURRENT STATUS

Macitentan is currently being further evaluated in multiple studies to expanding the clinical utility of this important product in PAH and beyond.

MAESTRO (MAcitentan in Eisenmenger Syndrome To RestOre exercise capacity) is a Phase III multi-center, double-blind, randomized, placebo-controlled, parallel-group study to evaluate the effects of macitentan on exercise capacity in patients with Eisenmenger Syndrome. This study is ongoing, with approximately 220 subjects to be randomized in a 1:1 ratio into 2 treatment groups (macitentan 10 mg or placebo) over a 16 week treatment period.

MERIT (Macitentan in thE tReatment of Inoperable chronic Thromboembolic pulmonary hypertension) is a Phase II prospective, randomized, placebo-controlled, double-blind, multi-center, parallel-group study to assess the efficacy, safety and tolerability of 10 mg macitentan in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). This study is ongoing, with approximately 78 subjects to be randomized in a 1:1 ratio into 2 treatment groups (macitentan 10 mg or placebo) over a 24 week treatment period.

At the end of 2015, the initial results of the Phase II MELODY study (Macitentan in subjects with combined prE- and post-capiLlary pulmOnary hypertension due to left ventricular DYsfunction) became available. MELODY was a prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group, 12-week study to evaluate the safety and tolerability of macitentan in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH). In this exploratory study, macitentan was generally well tolerated in the Group 2 pulmonary hypertension patient population with heart failure. In addition, encouraging hemodynamic effects were observed. The company is now fully evaluating the data and, together with the results of the current Phase II study with a new ERA, will make a decision on the future development strategy of Actelion's ERAs beyond PAH.

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 end of treatment (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 10 mg 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.

MILESTONES

2013 – Opsumit approved by the EU Commission
2013 – Opsumit approved by the US FDA
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. AAPS J 2012; 14(1):68-78.

 

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