ALLSCHWIL/BASEL, SWITZERLAND - Actelion (SIX: ATLN) today announced that the submission of the Marketing Authorisation Application (MAA) for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial hypertension to the EMA has been accepted. The EMA will now start the formal review process.

The United States Food and Drug Administration had already received the registration dossier on October 22nd 2012.

Macitentan, a novel oral dual endothelin receptor antagonist, was studied in the pivotal, long-term, event-driven Phase III outcome study, SERAPHIN, in which 742 patients suffering from pulmonary arterial hypertension were randomized to receive either placebo or macitentan at 3 mg or 10 mg once daily.

Treatment with macitentan has demonstrated a reduction in the risk of morbidity and mortality event over the treatment period versus placebo. This risk was reduced by 45 percent for patients in the 10 mg dose group (p<0.0001). The observed risk reduction was 30 percent (p=0.0108) for patients receiving the 3 mg dose.

Patients in SERAPHIN were treated for up to three and a half years, providing safety data which showed that macitentan was well tolerated. The most common adverse events associated with the use of macitentan were nasopharyngitis, headache and anemia.

Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "We have worked hard to prepare the dossiers for a timely submission to both Health Authorities and I am very happy that regulatory processes in both the United States and the European Union could be initiated. Actelion will continue to prepare for submissions in Switzerland and other major markets around the world."

About macitentan (Opsumit®)

Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process with the target to develop an ERA optimized for efficacy and safety [2]. Macitentan has a number of potentially key beneficial characteristics i.e., increased in vivo preclinical efficacy vs. existing ERAs resulting from sustained receptor binding [3] and physicochemical properties that allow an enhanced penetration into tissue [4]. The clinical pharmacology program indicated a low propensity of macitentan for drug-drug interactions [5,6,7]

About macitentan (Opsumit®) submissions to healthcare authorities

On 22nd October 2012 Actelion announced that it had submitted a new drug application to the US Food and Drug Administration (FDA) seeking approval for macitentan (Opsumit®) in patients with pulmonary arterial hypertension.

About 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 [1]. The pivotal Phase III study was designed to evaluate the efficacy and safety of macitentan (Opsumit®) - 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 and Latin America, Europe, Asia-Pacific and Africa and was completed in the first half of 2012, with 287 patients having an adjudicated event.

About Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of an affected individual. The symptoms of PAH are non-specific and can range from mild breathlessness and fatigue during normal daily activity to symptoms of right heart failure and severe restrictions on exercise capacity and ultimately reduced life expectancy.

PAH is one group within the classification of pulmonary hypertension (PH). This group includes idiopathic PAH, heritable PAH and PAH caused by factors which include connective tissue disease, HIV infection and congenital heart disease.

The last decade has seen significant advances in the understanding of the pathophysiology of PAH, which has been paralleled with developments of treatment guidelines and new therapies. Drugs targeting the 3 pathways that have been established in the pathogenesis of PAH are endothelin receptor antagonists (ERAs), prostacyclins and phosphodiesterase-5 inhibitors. PAH treatments have transformed the prognosis for PAH patients from symptomatic improvements in exercise tolerance 10 years ago to delayed disease progression today. Improved disease awareness and evidence-based guidelines developed from randomized controlled clinical trial data have highlighted the need for early intervention, goal-oriented treatment and combination therapy.

Despite these advances in PAH, survival rates are unacceptably low and PAH remains incurable.

References

1. For a general discussion of a clinically meaningful outcome end-point, please see: Proceedings of the 4th world symposium on pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl).
2. Bolli MH et al. The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist. J Med Chem. 2012; 55:7849-61.
3. Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O (2012). Slow Receptor Dissociation Kinetics Differentiate Macitentan from Other Endothelin Receptor Antagonists in Pulmonary Arterial Smooth Muscle Cells. PLOS ONE 7(10): e47662. doi:10.1371/journal.pone.0047662
4. Iglarz M et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736-45.
5. Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977-84
6. Bruderer S et al. Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans. Xenobiotica. 2012 Sep;42(9):901-10
7. Bruderer S et al. Effect of cyclosporine A and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist. AAPS J. 2012;14(1):68-78.

Actelion Ltd

Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium - the single layer of cells separating every blood vessel from the blood stream. Actelion's over 2,400 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).

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