Macitentan is a novel dual endothelin receptor antagonist that resulted from a tailored drug discovery process. Macitentan has a number of potentially key beneficial characteristics - i.e., increased in vivo preclinical efficacy vs. existing ERAs resulting from sustained receptor binding and tissue penetration properties. A clinical pharmacology program indicated a low propensity of macitentan for drug-drug interactions.

SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve clinical outcome) was the largest randomized, controlled study in PAH patients with a long-term treatment to include a clearly defined morbidity/mortality primary end-point [1]. The pivotal Phase III study was designed to evaluate the efficacy and safety of 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 eventdriven study was conducted in 151 centers, from almost 40 countries in North and Latin America, Europe, Asia-Pacific and Africa and was completed in the first half of 2012, with 287 patients having an adjudicated event.

In April 2012, Actelion announced that the pivotal Phase III SERAPHIN outcome study has met its primary endpoint.

Initial analysis indicated that in this long-term eventdriven study in patients with PAH, and treated for up to three and a half years, macitentan, at both the 3 mg and 10 mg dose, decreased the risk of a morbidity/ mortality event over the treatment period versus placebo. This risk was reduced by 45 percent in the 10 mg dose group (p<0.0001). At 3 mg, the observed risk reduction was 30 percent (p=0.0108).

Secondary efficacy endpoints including change from baseline to month 6 in six-minute walk-distance, change from baseline to month 6 in WHO functional class and time - over the whole treatment period - to either death due to PAH or hospitalization due to PAH also showed a dose-dependent effect (p<0.05 for either dose). A trend in favor of 10 mg macitentan was observed on all-cause mortality (p=ns).

Submission of the registration dossier to Health Authorities worldwide is expected by the fourth quarter of 2012.

Macitentan is currently investigated in a pivotal Phase III program in patients with ischemic digital ulcers associated with systemic sclerosis, initiated in December 2011. Additionally, following excellent preclinical results, a Phase I/Ib open-label study was initiated with macitentan in patients with recurring glioblastoma.

The safety set comprised 741 patients (randomized 1:1:1), who received at least one dose of study treatment. Mean exposure to study treatment was 85.3 weeks for placebo patients (n=249), 99.5 weeks for patients on 3 mg (n=250), and 103.9 weeks for patients on 10 mg (n=242).

Macitentan in this patient population was well tolerated. The number of adverse events reported and patients discontinuing treatment due to adverse events was similar across all groups.

Elevations of liver alanine or aspartate aminotransferases greater than three times the upper limit of normal were observed in 4.5 percent of patients receiving placebo, in 3.6 percent of patients on 3 mg of macitentan and in 3.4 percent of patients on 10 mg of macitentan. In addition, no difference was observed between macitentan and placebo on fluid retention (edema).

A decrease in hemoglobin - reported as an adverse event - was observed more frequently on macitentan than placebo, with no difference in treatment discontinuation between groups.

2012 – SERAPHIN outcome study meets its primary endpoint
2007 – Initiation of Phase III study SERAPHIN study in PAH patients
2005 – Initiation of Phase II dose ranging study
2004 – Entry-into-humans
2003 – Selection of Macitentan for initiation of preclinical studies

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Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol 2011;67(10):977-84.

Bruderer S et al. Effect of cyclosporine A and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J 2011 Dec 22 [Epub ahead of print].

Bruderer S et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Amer Coll of Clin Pharmacol 40thAnnual Meeting, Sep 11-13, 2011; Chicago, USA.