New macitentan (Opsumit) efficacy data in pulmonary arterial hypertension from SERAPHIN study presented at European Society of Cardiology Congress 2013
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Actelion Pharmaceuticals Ltd /
New macitentan (Opsumit) efficacy data in pulmonary arterial hypertension from
SERAPHIN study presented at European Society of Cardiology Congress 2013
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* Macitentan significantly reduced morbidity and mortality by 45% versus
placebo
* Macitentan treatment provides sustained long-term improvements in exercise
capacity
* No association found between changes in exercise capacity and long-term
clinical outcomes
* Improved cardiopulmonary hemodynamics seen in macitentan-treated patients
irrespective of baseline background pulmonary arterial hypertension (PAH)
therapy or WHO functional class
ALLSCHWIL/BASEL, SWITZERLAND - 02 September, 2013 - Actelion (SIX: ATLN) today
announced that new data for the investigational drug macitentan (Opsumit(®))
from the landmark SERAPHIN study was presented at the European Society of
Cardiology Annual Congress 2013 in Amsterdam, the Netherlands. The presentations
from leading experts in the field shared the latest findings on the impact of
macitentan on exercise capacity, long term outcome and cardiopulmonary
hemodynamics.
6MWD and long-term outcomes
In an oral presentation, Dr Nazzareno Galiè from the Institute of Cardiology,
University of Bologna, Bologna, Italy presented data evaluating the association
between 6MWD, a measure of exercise capacity and the long-term outcome measured
with the endpoint of PAH-related death or hospitalization in the SERAPHIN study.
Dr Galiè first shared that macitentan 10mg provided sustained long-term
improvements in 6-minute walk distance (6MWD) versus placebo over 12 months
(+25.4m, p<0.0001) and then discussed how 6MWD values at both baseline and month
6 were prognostic of long-term outcomes. Finally he showed data to demonstrate
that changes in 6MWD from baseline to Month 6 were not associated with PAH-
related death or hospitalization risk, raising important questions about the
link between functional improvements and long term treatment success.
Dr Galiè commented about data presented at the ESC Congress 2013, "The SERAPHIN
study is the first event-driven outcome trial in PAH to evaluate the association
between 6MWD and long-term outcomes. These data confirm the efficacy of
macitentan in improving the functional abilities of patients with PAH, as well
as to significantly improve patient outcome.
Dr Galiè added; "While our findings show that the absolute 6MWD value at
baseline is prognostic, there is no clear relationship between the change in
6MWD from baseline and long-term treatment outcomes. The study results confirm
that while the change in 6MWD is a useful marker of functional improvement, it
is not an appropriate measure when looking to understand the impact of treatment
on long-term morbidity and mortality. This observation reinforces the importance
of selecting appropriate outcome measures when investigating new treatment
options for our patients."
Hemodynamic effects of macitentan
Further evidence of the efficacy of macitentan was provided in a second oral
presentation, when
Dr Adam Torbicki of the Department of Pulmonary Circulation and Thromboembolic
Diseases, Center of Postgraduate Medical Education, ECZ-Otwock, Poland,
discussed the results of a substudy of SERAPHIN that investigated the impact of
macitentan on cardiopulmonary hemodynamics in pulmonary arterial hypertension.
Dr Torbicki commented; "Macitentan significantly improved hemodynamic parameters
overall in PAH patients in the SERAPHIN study. Furthermore, in our substudy,
consistent improvements in pulmonary vascular resistance (PVR) and cardiac index
(CI) were achieved with macitentan irrespective of background PAH therapy or
baseline WHO functional class."
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion also commented;
"We are delighted that once again the findings of the SERAPHIN study have
confirmed the efficacy of macitentan in making clinically relevant changes to
cardiopulmonary hemodynamics and easing the burden of patients with PAH. Dr
Galiè's confirmation that the change in 6MWD results are not linked to relevant
long-term outcomes in PAH reinforces the importance of the innovative approach
taken in SERAPHIN. The true efficacy of long-term treatments should be
established through the investigation of morbidity and mortality, because of
what matters most to our patients and physicians: reduce the progression of
PAH."
# # #
NOTES TO THE EDITOR
Oral Presentations at ESC Congress 2013
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
SERAPHIN trial
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
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 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
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
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). [1]
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 [3]. Macitentan has a number of
potentially key beneficial characteristics including increased in vivo
preclinical efficacy versus existing ERAs resulting from sustained receptor
binding [4] and physicochemical properties that allow enhanced tissue
penetration [5]. 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
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.
Despite these advances in PAH, survival rates are unacceptably low and PAH
remains incurable.
References
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.
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 Pharmacol Exp Ther.
2008;327(3):736-45.
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.
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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Datum: 02.09.2013 - 07:00 Uhr
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