Actelion Ltd : receives positive CHMP opinion for Opsumit (macitentan) for the long-term treatment of pulmonary arterial hypertension

• CHMP adopts positive opinion for Opsumit^® (macitentan), 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
   
• European Commission decision granting marketing authorization in the EU expected in two months

ALLSCHWIL, SWITZERLAND - 25 October 2013 - Actelion Ltd (SIX: ATLN) announced today that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), issued a positive opinion for the use of Opsumit^® (macitentan) 10mg for the treatment of pulmonary arterial hypertension (PAH).

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.

A CHMP positive opinion is one of the final steps before marketing authorization is granted by the European Commission. The European Commission is expected to issue a final decision in two months.

Dr Nazzareno Galiè from the Institute of Cardiology, University of Bologna, Bologna, Italy commented "With Opsumit^® we have the first demonstration of delayed disease progression in PAH patients over long-term. Opsumit^® was tested in the first ever outcome driven clinical trial from which we now have evidence that Opsumit^® is effective in both treatment naive patients as well as those already taking PDE5-inhibitors. The opinion of the CHMP today is a very encouraging step for patients with PAH."

The CHMP's positive opinion was based on the review of efficacy and safety data from the landmark phase III SERAPHIN study. Published in the New England Journal of Medicine in August 2013, the SERAPHIN study showed the risk of a morbidity/mortality event - the primary endpoint of the study - was reduced by 45% (p<0.0001) with macitentan 10mg compared to placebo. This effect was observed irrespective of whether or not patients were already treated with other therapies for PAH. SERAPHIN also showed a reduction in risk of PAH related hospitalization or death of 50% (p<0.0001) compared to placebo.

Gérald Simonneau M.D., Professor of Pneumology and Head of the Department of Pneumology and Intensive Care Unit, Hôpital Kremlin Bicêtre, Paris-Sud University, France, commented; "In 2008 we, the experts in the field of PAH, proposed that clinical trials used morbidity and mortality as a primary endpoint in future PAH studies. Today, Opsumit^®, is the first drug that was tested with this endpoint and it has now received a positive opinion from CHMP. I consider this as a turning point for PAH and believe that this robust and clinically relevant standard should be applied in all future clinical trials."

The most common adverse reactions observed in patients treated with Opsumit^® were anemia, nasopharyngitis / pharyngitis, bronchitis, headache, influenza, and urinary tract infection.

Opsumit^® is approved in the US, and has been submitted to regulatory bodies worldwide for the treatment of patients with PAH. Regulatory reviews by health authorities in other countries are ongoing.

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.

Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented, "We are delighted by the positive opinion issued by the CHMP on Opsumit^®. If approved, Opsumit^® could transform the lives of many people living with PAH. This positive opinion stands testament to the efforts of our development teams and our ongoing commitment to patients living with PAH."

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NOTES TO THE EDITOR

ABOUT OPSUMIT®(MACITENTAN)

Opsumit® (macitentan) is an orally available endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process with the target of developing an ERA to address efficacy and safety [3].

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 [2]. 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.

ABOUT SERAPHIN STUDY DATA

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. [1]

ABOUT THE SAFETY AND TOLERABILITY PROFILE

The most common adverse reactions observed in patients treated with Opsumit were anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection.

ABOUT OPSUMIT® (MACITENTAN) SUBMISSIONS TO HEALTHCARE AUTHORITIES

Approval of the new drug application for Opsumit® (macitentan) was issued by the US Food and Drug Administration (FDA) on 18October 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.

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 European Commission is expected to issue a final decision in two months.

Regulatory reviews are ongoing in Canada, Switzerland, Australia, Taiwan, Korea and Mexico.

ABOUT PULMONARY ARTERIAL HYPERTENSION [9, 10]

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 three 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.

In PAH, survival rates are unacceptably low and PAH remains incurable.

References

1. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013;369:809-18.
    
2. Proceedings of the 4th world symposium on pulmonary hypertension. J Am CollCardiol 2009;54(1 Suppl).
    
3. 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.
    
4. 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 
    
5. Iglarz M et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J PharmacolExpTher. 2008;327(3):736-45.
    
6. Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J ClinPharmacol. 2011;67(10):977-84
    
7. 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
    
8. 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.
    
9. Galiè N, Hoeper MM, Humbert M, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537
    
10. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from REVEAL. Chest 2012;142:448-56.

Actelion Ltd

Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer® (bosentan), 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®).

For further information please contact:

Roland Haefeli
Senior Vice President, Head of Investor Relations & Public Affairs
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
+1 650 624 69 36
www.actelion.com:
http://www.actelion.com/

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