2012-11-22 07:01:30 -
Actelion Pharmaceuticals Ltd /
Actelion submits the registration dossier for macitentan (Opsumit) to the
European Medicines Agency (EMA)
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ALLSCHWIL/BASEL, SWITZERLAND - 22 November 2012 - Actelion (SIX: ATLN) today
announced that the submission of the Marketing Authorisation Application (MAA)
for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial
hypertension to the EMA has been accepted. The EMA will now start the formal
review process.
The United States Food and Drug Administration had already received the
registration dossier on October 22(nd) 2012.
Macitentan, a novel oral dual endothelin receptor
antagonist, was studied in the
pivotal, long-term, event-driven Phase III outcome study, SERAPHIN, in which
742 patients suffering from pulmonary arterial hypertension were randomized to
receive either placebo or macitentan at 3 mg or 10 mg once daily.
Treatment with macitentan has demonstrated a reduction in the risk of morbidity
and mortality event over the treatment period versus placebo. This risk was
reduced by 45 percent for patients in the 10 mg dose group (p<0.0001). The
observed risk reduction was 30 percent (p=0.0108) for patients receiving the
3 mg dose.
Patients in SERAPHIN were treated for up to three and a half years, providing
safety data which showed that macitentan was well tolerated. The most common
adverse events associated with the use of macitentan were nasopharyngitis,
headache and anemia.
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "We
have worked hard to prepare the dossiers for a timely submission to both Health
Authorities and I am very happy that regulatory processes in both the United
States and the European Union could be initiated. Actelion will continue to
prepare for submissions in Switzerland and other major markets around the
world."
# # #
About macitentan (Opsumit®)
Macitentan (Opsumit®) is a novel dual endothelin receptor antagonist (ERA) that
resulted from a tailored drug discovery process with the target to develop an
ERA optimized for efficacy and safety [2]. Macitentan has a number of
potentially key beneficial characteristics i.e., increased in vivo preclinical
efficacy vs. existing ERAs resulting from sustained receptor binding [3] and
physicochemical properties that allow an enhanced penetration into tissue [4].
The clinical pharmacology program indicated a low propensity of macitentan for
drug-drug interactions [5,6,7]
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.
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 [1]. 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 and Latin America, Europe, Asia-Pacific and Africa and was
completed in the first half of 2012, with 287 patients having an adjudicated
event.
About Pulmonary Arterial Hypertension
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 3 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
remains incurable.
References
1. 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).
2. 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.
3. 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
4. Iglarz M et al. Pharmacology of macitentan, an orally active tissue-
targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther.
2008;327(3):736-45.
5. Sidharta PN et al. Macitentan: Entry-into-humans study with a new endothelin
receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977-84
6. 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
7. 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.
Actelion Ltd
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in
Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, 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 2,400 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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