Actelion Announces U.S. Commercial Availability of OPSUMIT® (macitentan) as of November 4

  Actelion 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

Business Wire

SOUTH SAN FRANCISCO -- November 4, 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 WHOFunctional Class II-III symptoms treated for an average of
2years. 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 by3% 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.

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 counseled 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%) 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 Tet al.Macitentan and Morbidity and Mortality in Pulmonary
    Arterial Hypertension.NEngl J Med2013;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 Tet al.Macitentan and Morbidity and Mortality in Pulmonary
    Arterial Hypertension.N Engl J Med2013;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.

Contact:

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