Actelion Ltd : receives Health Canada approval of Opsumit (macitentan) for the long-term treatment of pulmonary arterial hypertension

ALLSCHWIL, SWITZERLAND - 12 NOVEMBER 2013 - Actelion Ltd (SIX: ATLN) announced today that Health Canada has granted a Notice of Compliance (NOC) approving the orally available endothelin receptor antagonist Opsumit^TM (macitentan) 10 mg once daily for the treatment of pulmonary arterial hypertension (PAH). 

Opsumit (macitentan) is indicated in Canada, for the long-term treatment of pulmonary arterial hypertension (PAH, WHO Group l) to reduce morbidity in patients of WHO Functional Class II or III whose PAH is either idiopathic or heritable, or associated with connective tissue disease or congenital heart disease. 

Opsumit is effective when used as monotherapy or in combination with phosphodiesterase-5 inhibitors. 

Dr. Sanjay Mehta, MD, FRCPC, FCCP, Professor of Medicine at Western University, Director of the Southwest Ontario Pulmonary Hypertension Clinic at the London Health Sciences Center in London, Ontario and Chair of the Pulmonary Hypertension Association of Canada commented: "This new study represents a critical milestone in the treatment of PAH patients. We now have a new standard of excellence for clinical trials in PAH and the strongest evidence ever of hope for long-term improved quality of life and clinical stability for those affected by PAH in Canada." 

Dr Mehta, who was also a SERAPHIN investigator and co-author of the published article in the New England Journal of Medicine continued: "Five years ago, global and Canadian experts in PAH proposed that future PAH clinical studies should assess the effects of treatment on long-term morbidity and mortality, a clinically more important primary endpoint compared to all previous studies, which only looked at very short-term outcomes, such as the six minute walk test. Today, thanks to Opsumit, we now have an answer to this critical question of long-term benefits of PAH treatment on clinical outcomes important to patients." 

Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "The approval by Health Canada for Opsumit is another milestone for Actelion. In just a few short weeks we have seen the approval of Opsumit in both the US and Canada along with the positive CHMP decision in Europe showing Actelion's efficiency and expertise in managing the submissions for Opsumit." 

The most common adverse reactions observed with Opsumit (>3% compared to placebo) are nasopharyngitis, headache, anemia, bronchitis, urinary tract infection, pharyngitis and influenza. 

It is recommended that hemoglobin concentrations are measured prior to initiation of treatment with Opsumit, again after one month, and periodically thereafter as clinically indicated. Liver enzyme tests should be obtained prior to initiation of Opsumit. Subsequently, monthly testing during the first year of treatment is recommended. They may then be repeated less frequently during treatment as clinically indicated. 

Actelion expects Opsumitto become available to patients by early 2014 in Canada. 

Actelion continues to work with other health authorities worldwide to obtain regulatory approval for Opsumit. 

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.

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NOTES TO THE EDITOR

ABOUT OPSUMIT^TM (MACITENTAN)

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 [1].

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 enrolment 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. [3]

ABOUT THE SAFETY AND TOLERABILITY PROFILE

Opsumit is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container; women who are or may become pregnant and nursing women.

Physicians are advised to measure hemoglobin prior to initiation of treatment, again after one month, and periodically thereafter as clinically indicated. Liver enzyme blood tests should be obtained prior to initiation of Opsumit, and monthly testing during the first year of treatment is recommended and then less frequently thereafter as clinically indicated.

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 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). Opsumit also reduced hospitalization for PAH.

On October 25, 2013, the CHMP recommended that the European Commission approve 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. Regulatory reviews are ongoing in, Switzerland, Australia, Taiwan, Korea and Mexico.

ABOUT PULMONARY ARTERIAL HYPERTENSION [4, 5]

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. 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.
2. Proceedings of the 4th world symposium on pulmonary hypertension. J Am CollCardiol 2009;54(1 Suppl).
3. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013;369:809-18.
4. 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.
5. 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 2,300 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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