2013-08-31 11:02:01 -
Actelion Pharmaceuticals Ltd /
Further macitentan (Opsumit) data in pulmonary arterial hypertension presented
at key congresses
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The issuer is solely responsible for the content of this announcement.
ALLSCHWIL/BASEL, SWITZERLAND - 31 August 2013 - Actelion Ltd (SIX: ATLN) today
announced that further data on its investigational drug macitentan (Opsumit(®))
from the SERAPHIN study will be presented at the European Society of Cardiology
(ESC) Congress 2013 in Amsterdam, the Netherlands (31(st) August-4(th) September
2013) and the European Respiratory Society (ERS) Annual Congress in Barcelona,
Spain (7(th)-11(th) September 2013).
Data to be presented at ESC Congress 2013
Dr Nazzareno Galiè from the Institute of Cardiology, University of Bologna,
Bologna, Italy, will give an
oral presentation entitled 'Sustained effect of
macitentan, a novel oral endothelin receptor antagonist, on exercise capacity
and the association of its measure with long-term outcomes in pulmonary arterial
hypertension' at 11:00 on September 1(st) during the session 'Advances in Drug
Therapy for PAH'.
Dr Adam Torbicki of the Department of Pulmonary Circulation and Thromboembolic
Diseases, Center of Postgraduate Medical Education, ECZ-Otwock, Poland, will
also make an oral presentation 'Effect of macitentan on haemodynamics in
patients with pulmonary arterial hypertension: results from the long-term,
randomised, placebo-controlled SERAPHIN trial' at 11:15 on September 1(st) in
the same session.
Data to be presented at ERS Congress 2013
Professor Hossein-Ardeschir Ghofrani from the University Hospital Giessen,
Giessen, Germany, will give an oral presentation entitled 'Effect of macitentan
on morbidity and mortality in pulmonary arterial hypertension: a randomised
controlled trial' during the 'Pulmonary circulation: treatment' session at
10:00 on September 9(th).
Professor Marion Delcroix of Gasthuisberg University Hospital, Leuven, Belgium
will present a poster entitled 'Is 6-minute walk distance (6MWD) associated with
long-term outcomes in pulmonary arterial hypertension (PAH)? Results from
SERAPHIN' during the 'Pulmonary circulation: clinical science and treatment'
session at 08:30 on September 10(th).
Professor Olivier Sitbon of the Hôpital Universitaire de Bicêtre, Université
Paris-Sud, Paris, France will present a poster on the 'Effect of macitentan on
haemodynamics in SERAPHIN, a randomised controlled trial in pulmonary arterial
hypertension (PAH)' during the Pulmonary circulation: clinical treatment poster
session at 12:50 on September 10(th).
Professor Pavel Jansa of Charles University, Prague, Czech Republic will present
the poster 'Impact of macitentan on the health-related quality of life (HRQoL)
in pulmonary arterial hypertension (PAH): results from a long-term randomised
controlled trial' during the Pulmonary circulation: clinical treatment poster
session at 12:50 on September 10(th).
# # #
NOTES TO THE EDITOR
Sustained effect of macitentan, a novel oral endothelin receptor antagonist, on
exercise capacity and the association of its measure with long-term outcomes in
pulmonary arterial hypertension.
N Galiè, R Channick, M Delcroix, H-A Ghofrani, P Jansa, F-O Le Brun, G
Simmoneau, LJ Rubin
Oral abstract presentation: September 01, 11.00-11.15
Abstract Number: 1061
Effect of macitentan on haemodynamics in patients with pulmonary arterial
hypertension: results from the long-term, randomised, placebo-controlled
A Torbicki, S Mehta, L Perchenet, T Pulido, BKS Sastry, O Sitbon, R Souza, LJ
Rubin, G Simmoneau
Oral abstract presentation: September 01, 11.15-11.30
Abstract Number: 1062
ERS CONGRESS 2013 ABSTRACTS
Effect of macitentan on morbidity and mortality in pulmonary arterial
hypertension: a randomised controlled trial
H-A Ghofrani, R Channick, M Delcroix, N Galiè, P Jansa, F-O Le Brun, S Mehta, C
Mittelholzer, T Pulido, BKS Sastry, O Sitbon, R Souza, O Sitbon, A Torbicki,L
Rubin, G Simmoneau
Oral presentation: September 09, 10.00-10.15
Abstract Number: 850897
Is 6-minute walk distance (6MWD) associated with long-term outcomes in pulmonary
arterial hypertension (PAH)? Results from SERAPHIN
M Delcroix, R Channick, N Galiè, H-A Ghofrani, P Jansa, F-O Le Brun, S Mehta, L
Perchenet, T Pulido, BKS Sastry, O Sitbon, R Souza, A Torbicki, G Simmoneau
Poster discussion: September 10, 08.30-10.00
Abstract Number: 851571
Impact of macitentan on the health-related quality of life (HRQoL) in pulmonary
arterial hypertension (PAH): results from a long-term randomised controlled
P Jansa, R Channick, M Delcroix, N Galiè, H-A Ghofrani, E Hunche, S Mehta, C
Mittelholzer, T Pulido, BKS Sastry, O Sitbon, R Souza, A Torbicki, G Simmoneau,
Poster: September 10, 12:50-14:40
Abstract Number: 850697
Effect of macitentan on haemodynamics in SERAPHIN, a randomised controlled trial
in pulmonary arterial hypertension (PAH)
O Sitbon, R Channick, M Delcroix, N Galiè, H-A Ghofrani, P Jansa, F-O Le Brun, S
Mehta, L Perchenet, T Pulido, BKS Sastry, R Souza, A Torbicki, L Rubin, G
Poster: September 10, 12:50-14:40
Abstract Number: 854762
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 . The pivotal Phase III study was
designed to evaluate the efficacy and safety of macitentan (Opsumit®) - 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
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.
ABOUT THE SAFETY AND TOLERABILITY PROFILE
Macitentan was well tolerated in the SERAPHIN study. The overall incidence of
adverse events reported and treatment discontinuations due to adverse events in
patients was similar across all groups. The incidence of serious adverse events
was lower in patients treated with macitentan compared to placebo, with 52% and
45% of patients in the macitentan 3 mg and 10 mg groups respectively, and 55% of
patients in the placebo group experiencing serious adverse events.
Compared with placebo, a higher proportion of macitentan-treated patients had
nasopharyngitis, headache, and anemia. One patient in each treatment group
discontinued due to anemia.
Elevations of liver alanine or aspartate aminotransferases greater than three
times the upper limit of normal were observed in 4.5 percent of patients
receiving placebo, 3.4 percent of patients on 10 mg of macitentan and in
3.6 percent of patients on 3 mg of macitentan. In addition, no difference in
fluid retention (edema) was observed between macitentan and placebo. 
ABOUT MACITENTAN (OPSUMIT®)
Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) that
resulted from a tailored drug discovery process with the target of developing an
ERA optimized for efficacy and safety . Macitentan has a number of
potentially key beneficial characteristics including increased in vivo
preclinical efficacy versus existing ERAs resulting from sustained receptor
binding  and physicochemical properties that allow enhanced tissue
penetration . The clinical pharmacology program also indicated a low
propensity of macitentan for drug-drug interactions [6,7,8] .
ABOUT MACITENTAN (OPSUMIT®) SUBMISSIONS TO HEALTHCARE AUTHORITIES
On 22(nd) October 2012 Actelion announced that it had submitted a new drug
application to the US Food and Drug Administration (FDA) seeking approval for
macitentan (Opsumit®) in patients with pulmonary arterial hypertension.
On 22(nd) November 2012 Actelion announced that it had successfully submitted
the Market Authorisation Application to the European Medicines Agency (EMA) and
a validation letter had been received.
Regulatory review is also ongoing in Canada, Switzerland, Australia, Taiwan and
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.
Despite these advances in PAH, survival rates are unacceptably low and PAH
1. Pulido T et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial
Hypertension. N Engl J Med 2013;369:809-18.
2. For a general discussion of a clinically meaningful outcome end-point,
please see: Proceedings of the 4th world symposium on pulmonary
hypertension. J Am Coll Cardiol 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.
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 Pharmacol Exp Ther.
6. Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin
receptor antagonist. Eur J Clin Pharmacol. 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.
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 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
For further information please contact:
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
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