2013-08-29 07:04:03 -
Actelion Pharmaceuticals Ltd /
The New England Journal of Medicine publishes macitentan (Opsumit) morbidity and
mortality study in pulmonary arterial hypertension
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* Macitentan (Opsumit(®)) significantly reduced risk of morbidity/mortality
* Macitentan currently in world-wide regulatory review
ALLSCHWIL / BASEL, SWITZERLAND - 29 August 2013 - Actelion (SIX: ATLN)
announced today that the New England Journal of Medicine (NEJM) has published
the results of SERAPHIN, the pivotal study with macitentan (Opsumit(®)) in
patients with pulmonary arterial hypertension (PAH).
Dr Tomás Pulido,
MD, Professor of Medicine and Head of the Cardiopulmonary
Department, Ignacio Chávez National Heart Institute, Mexico City, primary author
of the NEJM paper, commented: "I am very proud to be part of this exceptional
study. The results published today in the NEJM show valuable long-term
morbidity/mortality data from SERAPHIN, the largest-ever trial in PAH. I expect
this landmark study to set a new standard in how the evidence for PAH therapies
The NEJM paper reports the findings of the SERAPHIN study, a Phase III trial in
which 742 patients received either macitentan or placebo. The risk of a
morbidity/mortality event - primary endpoint of the study - was reduced by 45%
(p<0.001) with macitentan 10mg compared to placebo.
Dr Pulido concluded: "The SERAPHIN study considered several indicators of PAH
progression in a robustly defined endpoint and demonstrated that macitentan
significantly reduced the risk of morbidity and mortality in both treatment-
naïve patients and those on background therapy for PAH."
The effect of macitentan on the primary endpoint was observed irrespective of
whether or not patients were already treated with other therapies for PAH. About
two thirds of the patients were taking phosphodiesterase-5 inhibitors when they
entered the study. Macitentan was well tolerated in the SERAPHIN study. 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.
Gérald Simonneau M.D., Professor of Pneumology and Head of the Department of
Pneumology and Intensive Care Unit, Hôpital Kremlin Bicêtre, Paris-Sud
University, France, advisor on SERAPHIN and a senior author of the paper,
commented: "The data published today are very exciting. It is relevant for both
patients and physicians treating PAH. It is the first time we have seen data on
patients evaluated over such a long period of time with outcome as a primary
focus. The results suggest that macitentan, upon approval, has the potential to
offer a new treatment option for PAH physicians and our patients."
A significant treatment effect was also observed on the combined secondary
outcome measure of the impact of macitentan on PAH-related hospitalization and
death. The 10mg macitentan treatment group showed a reduction in risk of
hospitalization and death of 50% p<0.001 compared to placebo.
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. In the last decade, major advances in treatment have led to
improvements in some measures of patient outcomes. Despite these advances in
PAH, survival rates are unacceptably low and PAH remains incurable.
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented:
"Today's publication in the New England Journal of Medicine illustrates what can
be achieved by combining high quality drug discovery with comprehensive clinical
development. Very importantly this publication was only made possible by the
unwavering commitment of the PAH community. The data from this positive study
with macitentan provide the basis for the ongoing worldwide regulatory filings
and we will continue to work with the Health Authorities to help bring this
potentially important treatment for PAH to patients as soon as possible."
# # #
NOTES TO THE EDITOR
ABOUT THE STUDY DATA PUBLISHED IN THE NEJM
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=0.01) and the
hazard ratio for macitentan 10 mg versus placebo was 0.55 (97.5% CI, 0.39 to
0.76; p<0.001). 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 REPORTED IN NEJM
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 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 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 Authorization 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:
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Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
+1 650 624 69 36
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