Actelion Ltd : announces U.S. commercial availability of opsumit (macitentan) as of November 4

• OPSUMIT -- indicated to delay disease progression and reduced hospitalizations in pulmonary arterial hypertension -- now available to patients

SOUTH SAN FRANCISCO - 4 November 2013 - Actelion (SIX: ATLN) today announced the commercial availability of OPSUMIT® (macitentan) 10mg, an oral, dual endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression. PAH is a chronic, life-threatening disorder that can severely compromise the function of the lungs and heart. The U.S. Food and Drug Administration (FDA) approved OPSUMIT on October 18, 2013.

OPSUMIT® is indicated 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.

Effectiveness was established in a long-term study in PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of 2 years. Patients were treated with OPSUMIT monotherapy or in combination with phosphodiesterase-5 inhibitors or inhaled prostanoids. Patients had idiopathic and heritable PAH (57%), PAH caused by connective tissue disorders (31%), and PAH caused by congenital heart disease with repaired shunts (8%).

"OPSUMIT is a clinically proven treatment option that is the first drug to demonstrate, in a randomized, controlled study, delay in disease progression for PAH over the long term. I am very pleased to be able to offer my patients suffering from this debilitating disease a new treatment option," said Richard Channick, MD, director, Pulmonary Hypertension and Thromboendarterectomy Program, Massachusetts General Hospital, Boston.*

"The availability of OPSUMIT in the U.S. marks a significant milestone for physicians and patients. They now have a treatment option available that is shown to improve both short-term physical functioning and long-term PAH outcomes," said Bill Fairey, president of Actelion Pharmaceuticals U.S. "Actelion is committed to bringing this important treatment to patients suffering from PAH and has therefore established a patient support program to provide access to OPSUMIT." 

"All of us at the Pulmonary Hypertension Association are excited when new treatments become available.  We know that not all treatments work for all patients and having new options - whether used alone or in combination with other therapies - means that physicians have more opportunities for helping their patients," said Rino Aldrighetti, president and CEO of the Pulmonary Hypertension Association.

The efficacy of OPSUMIT was established in the SERAPHIN study, a long-term study of 742 PAH patients with predominantly WHO Functional Class II-III symptoms treated for an average of two years. OPSUMIT is the only oral PAH treatment that has proven efficacy on long-term PAH outcomes and hospitalizations. [1]

Opsumit® carries a Boxed Warning alerting patients and health care professionals that the drug should not be used in pregnant women because it can harm the developing fetus. Female patients can receive the drug only through the Opsumit REMS Program. All female patients must be enrolled in the program, comply with pregnancy testing requirements and be counseled regarding the need for contraception.

The most common adverse reactions (more frequent than placebo by 3% or more) observed in patients treated with Opsumit® were anemia, nasopharyngitis/pharyngitis, bronchitis, headache, influenza, and urinary tract infection.

Physicians are advised to measure hemoglobin and liver enzymes prior to initiation of Opsumit® and repeat during treatment as clinically indicated.

OPSUMIT is available in 10 mg tablets for once-daily oral administration.  Full prescribing information can be found on the product website at www.Opsumit.com.

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NOTES TO THE EDITOR

ABOUT OPSUMIT® (MACITENTAN)

OPSUMIT® (macitentan) is a 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 [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 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

Opsumit® carries a Boxed Warning alerting patients and health care professionals that the drug should not be used in pregnant women because it can harm the developing fetus. Female patients can receive the drug only through the Opsumit REMS Program. All female patients must be enrolled in the program, comply with pregnancy testing requirements and be counseled regarding the need for contraception.

OPSUMIT is contraindicated in pregnancy because it may harm the developing fetus. Females of reproductive potential should be counselled on the use of reliable contraception and have a negative pregnancy test prior to initiating therapy and monthly thereafter.

Other ERAs have been associated with elevations of aminotransferases, hepatotoxicity, and liver failure. Liver enzyme tests should be obtained prior to initiation of OPSUMIT® and repeated during treatment as clinically indicated. If clinically relevant aminotransferase elevations occur, or if elevations are accompanied by clinical symptoms of hepatoxicity, discontinue OPSUMIT®.

Decreases in hemoglobin concentration and hematocrit occurred following administration of other ERAs and were observed in clinical studies with OPSUMIT. The decreases occurred early and stabilized thereafter. Decreases in hemoglobin seldom require transfusion. Initiation of OPSUMIT® is not recommended in patients with severe anemia. Hemoglobin should be measured prior to initiation of treatment and repeat during treatment as clinically indicated.

Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue OPSUMIT®.

Other ERAs have been associated with adverse effects on spermatogenesis.  Men should be counseled about potential effects on fertility.

The use of OPSUMIT® with strong CYP3A4 inducers or inhibitors should be avoided.

The most common adverse reactions (more frequent than placebo by 3% or more) 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). The need for PAH hospitalization was also reduced.

Regulatory reviews are ongoing in Europe, 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

*Dr. Channick is a member of the SERAPHIN Steering Committee and has been a consultant for Actelion, the sponsor of the study and manufacturer of Opsumit.

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.
11. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013;369:809-18.
12. 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.
13. 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
14. Iglarz M et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J PharmacolExpTher. 2008;327(3):736-45.
15. Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin receptor antagonist. Eur J ClinPharmacol. 2011;67(10):977-84
16. 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
17. 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.

For further information please contact:

Susan Neath 
W2O Group for Actelion Ltd 
609-529-0676
sneath@w2ogroup.com