Actelion Pharmaceuticals Ltd: Actelion receives US FDA approval of Opsumit (macitentan) for the treatment of pulmonary arterial

  Actelion Pharmaceuticals Ltd: Actelion receives US FDA approval of Opsumit
      (macitentan) for the treatment of pulmonary arterial hypertension

Actelion Pharmaceuticals Ltd / Actelion receives US FDA approval of Opsumit
(macitentan) for the treatment of pulmonary arterial hypertension . Processed
and transmitted by Thomson Reuters ONE. The issuer is solely responsible for
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ALLSCHWIL, SWITZERLAND - 18 OCTOBER 2013 - Actelion Ltd (SIX: ATLN)  announced 
today that the United States Food  and Drug Administration (FDA) has  approved 
the use  of the  orally available  endothelin receptor  antagonist  Opsumit^® 
(macitentan)  10mg  once  daily  for  the  treatment  of  pulmonary  arterial 
hypertension (PAH) to delay disease progression.

Opsumit is  indicated for  the treatment  of pulmonary  arterial  hypertension 
(PAH, WHO GroupI) 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%).

Dr. Vallerie McLaughlin, Director of the Pulmonary Hypertension Program in the
Division of Cardiovascular Medicine at the University of Michigan,  commented: 
"Over the past  twenty years,  great strides have  been made  in treating  PAH 
patients. However, there  has been  a medical need  for innovative  treatments 
that improve long-term outcomes. Opsumit^® is the first clinically proven  and 
only oral treatment option indicated  to delay disease progression and  reduce 
the need for PAH hospitalization."

Dr. McLaughlin concluded:  "These effects were  demonstrated in SERAPHIN,  the 
first and largest  PAH outcome  study to date,  where Opsumit^®  was given  on 
average  for   2   years,   as   a  monotherapy   or   in   combination   with 
phosphodiesterase-5 inhibitors or inhaled prostanoids. I am very pleased  that 
PAH patients will have this new treatment option."

Jean-Paul Clozel,  M.D. and  Chief Executive  Officer of  Actelion  commented: 
"Today's approval of Opsumit^® by the FDA is providing the PAH community  with 
a unique treatment option, the only oral PAH medicine that has proven to delay
disease progression. Over the last 14 years, Actelion has worked tirelessly to
first discover  and  then  develop  Opsumit^®  in  the  largest,  longest  and 
first-ever outcome study in PAH. I would  like to express my gratitude to  all 
the members of the PAH community. Without their contribution, Opsumit^®  would 
not have become a reality. We will now leverage our existing PAH expertise and
infrastructure to bring Opsumit^® to patients within the coming weeks."  

The US  label for  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  counselled 
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.

In the  United  States, Actelion  expects  Opsumit^® to  become  available  to 
patients in November. Outside of the United States, Actelion continues to work
with health authorities to obtain regulatory approval for Opsumit^® .

The FDA  approval was  based  in part  on 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  the first  occurrence  of  a 
morbidity or mortality event, the primary  endpoint of the study, was  reduced 
by 45% (p<0.0001) with macitentan 10  mg 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 risk reduction in PAH  related 
hospitalization and death of 50% (p<0.0001) compared to placebo. ^[1].

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.

                                     ###

NOTES TO THE EDITOR

ABOUT OPSUMIT®(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 [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.

Dr. McLaughlin is  a consultant  to Actelion and  was an  investigator in  the 
SERAPHIN trial.

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 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 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.

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

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.



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



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