Actelion announces results of the MAESTRO study with macitentan in patients with pulmonary arterial hypertension due to Eisenmenger Syndrome
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Actelion Pharmaceuticals Ltd /
Actelion announces results of the MAESTRO study with macitentan in patients with
pulmonary arterial hypertension due to Eisenmenger Syndrome
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The issuer is solely responsible for the content of this announcement.
ALLSCHWIL/BASEL, SWITZERLAND - 23 January 2017 - Actelion Ltd (SIX: ATLN) today
announced that the MAESTRO study to assess the efficacy, safety and tolerability
of macitentan in patients with pulmonary arterial hypertension (PAH) due to
Eisenmenger Syndrome did not meet its primary objective.
Professor Nazzareno Galiè, Head of the Pulmonary Hypertension Center at the
Institute of Cardiology, University of Bologna, and Steering Committee member
for the MAESTRO study, commented: "The results of the MAESTRO study are very
difficult to interpret. We have seen encouraging positive effects of macitentan
in the response of N-terminal pro b-type natriuretic peptide plasma levels and
hemodynamic measures. Although the results point towards a benefit of treatment
with macitentan, we do not see a significant treatment effect on the primary
endpoint of exercise capacity as measured in the 6 minute walk test. I believe
this has been influenced by an unexpected improvement in the placebo arm of the
study, which is unusual in a predominantly untreated PAH population. In fact, we
have not seen such a persistent placebo effect in the multiple studies published
so far in PAH. We need to fully analyze the data to understand what could have
caused this phenomenon."
In MAESTRO, 226 patients, including 135 patients in Functional Class II, were
randomized in a 1:1 ratio to receive either 10 mg macitentan or placebo once
daily. After 16 weeks of treatment, the mean change in 6-minute walk distance
(6-MWD) from baseline was an increase of 18.3 meters (m) in the macitentan group
and 19.7 m in the placebo group. The 6-MWD least-squares mean difference at Week
16 was -4.7 m between macitentan and placebo (95% CL: -22.8, 13.5 m; p=0.612,
intention-to-treat (ITT)). There were 3 patients with missing 6-MWD values at
Week 16 in the macitentan group, and imputation of zero meters at Week 16 was
applied. In the per-protocol population (200 patients), the mean change in 6-MWD
from baseline was an increase of 30.2 m in the macitentan group and 18.9 m in
the placebo group. The 6-MWD least-squares mean difference at Week 16 was 6.4 m
between macitentan and placebo (95% CL: -7.0, 19.8 m; p=0.347 per-protocol).
A 20% reduction of the exploratory biomarker endpoint, N-terminal pro b-type
natriuretic peptide, an indicator of cardiac response, was observed after 16
weeks with macitentan compared to placebo (95% CL: -32%, -6%; p=0.006) in the
overall patient population. In addition, a 13% reduction in pulmonary vascular
resistance index (PVRi) was observed after 16 weeks with macitentan compared to
placebo (95% CL: -27%, 3%; p=0.102 ITT) in a hemodynamic sub-study of 39
patients (20 in the macitentan group and 19 in the placebo group). The mean
change from baseline to Week 16 in PVRi was a decrease of -409.8 dyn.sec/cm5/m2
in the macitentan group and an increase of 79.4 dyn.sec/cm5/m2 in the placebo
group. The PVRi least-squares mean difference at Week 16 was -434.8
dyn.sec/cm5/m2 between macitentan and placebo (95% CL: -791.5, -78.0 m; p=0.018,
ITT). Patients in the sub-study also showed an improvement in exercise capacity:
the mean change in 6-MWD from baseline was an increase of 34.1 m in the
macitentan group and 3.5 m in the placebo group. The 6-MWD least-squares mean
difference at Week 16 was 24.9 m between macitentan and placebo (95% CL: -9.1,
59.0 m; p=0.146 ITT).
Guy Braunstein, Head of Global Clinical Development, commented: "We have seen
encouraging results on multiple measures, particularly in the hemodynamic sub-
study. Preliminary results from the open label extension of the study suggest
that patients originally randomized to placebo and subsequently treated with
macitentan showed an improvement in exercise capacity after 24 weeks. We must
fully understand the results, in particular the reason for the large placebo
effect, to know what might be changed so that we can deliver on our commitment
to patients with Eisenmenger Syndrome."
The MAESTRO safety set comprised 226 patients, 114 patients in the macitentan
group and 112 patients in the placebo group. Macitentan was well tolerated in
this patient population, and safety was, in general, consistent with the known
safety profile for macitentan from previous clinical studies. The most
frequently reported adverse events that occurred with higher frequency on
macitentan vs. placebo were headache (11.4% vs. 4.5%) and upper respiratory
tract infection (9.6% vs. 6.3%). Seven (6.1%) patients on macitentan experienced
a serious adverse event compared with two (1.8%) patients on placebo. Two
patients (1.8%) in each group discontinued the study treatment due to an adverse
event. During the course of the study, there was one death reported (respiratory
failure), in a patient receiving macitentan.
The company will now fully analyze the data and make them available through a
peer-reviewed publication.
ABOUT EISENMENGER SYNDROME
Eisenmenger Syndrome represents the most advanced form of pulmonary arterial
hypertension in conjunction with congenital heart disease (PAH-CHD). The
congenital heart defect causes a shunt to develop between two chambers of the
heart, so an increased blood flow returns to the lungs. The blood vessels in the
lung arteries become stiff and narrow, resulting in pulmonary hypertension.
Eisenmenger Syndrome occurs when the pressure in the pulmonary circulation
becomes so great that the direction of blood flow through the shunt reverses. It
is associated with the development of chronic cyanosis and limited exercise
capacity.
Patients with Down Syndrome represent between 25% and 50% of the Eisenmenger
population, depending on cohort studied. To address the high unmet medical need
for effective, targeted PAH therapies in this vulnerable population, Actelion
extended the MAESTRO study with macitentan in Eisenmenger Syndrome patients to
the Down Syndrome community. To ensure proper safeguards were established to
protect the patients' rights and safety, the company worked with ethics
committees, patient advocacy, support groups and patients' families.
ABOUT THE MAESTRO STUDY
MAESTRO (MAcitentan in Eisenmenger Syndrome To RestOre exercise capacity) was a
Phase III multi-center, double-blind, randomized, placebo-controlled, parallel-
group study to evaluate the effects of macitentan on exercise capacity in
patients with Eisenmenger Syndrome. The study was started in 2013 and global
enrollment was completed in August 2016 with a total of 226 patients. Patients
were randomized in a 1:1 ratio, with 114 patients in the macitentan 10 mg group
and 112 patients in the placebo group over a 16-week treatment period. The study
was conducted in 71 centers in 26 countries. The regions included North and
Latin America, Europe, and Asia-Pacific. A sub-study was conducted in 8
countries and 11 centers to evaluate the effects of macitentan on hemodynamic
parameters assessed by cardiac catheterization in patients with Eisenmenger
Syndrome.
MAESTRO included 135 (59.7%) patients earlier in the course of the disease
(Functional Class II) as well as 62 (27.4%) patients who received a PDE-5
inhibitor as background therapy. MAESTRO is one of the first randomized clinical
trials in Eisenmenger to include patients with Down Syndrome. 20 (8.8%) patients
with Down Syndrome were enrolled in the study, contributing to the broader
advancement of knowledge and understanding of this disease.
###
Notes to the Editor
ABOUT OPSUMIT(®) (MACITENTAN)
Opsumit (macitentan), an orally available endothelin receptor antagonist,
resulted from a tailored drug discovery process in Actelion's laboratories.
In the US, Opsumit is indicated for the treatment of 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). Opsumit also reduced hospitalization for PAH.
Effectiveness was established in a long-term study in PAH patients with
predominantly WHO FC 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%).
In Europe, Opsumit is indicated, as monotherapy or in combination, for the long-
term treatment of PAH in adult patients of WHO Functional Class (FC) II to III.
Efficacy has been shown in a PAH population including idiopathic and heritable
PAH, PAH associated with connective tissue disorders, and PAH associated with
corrected simple congenital heart disease.
Opsumit is very likely to cause major birth defects. It is contraindicated for
use in pregnancy. In the US, Opsumit is distributed under a risk evaluation and
mitigation strategy.
AVAILABLE CLINICAL DATA
SERAPHIN, a global, pivotal Phase III study, was designed to evaluate the
efficacy and safety of macitentan in patients with symptomatic PAH, through the
primary endpoint of time to first morbidity and all-cause mortality event. A
total of 742 patients were randomized to placebo (n=250), macitentan 3 mg
(n=250), or macitentan 10 mg (n=242). The primary endpoint 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 endpoint event. Patients were allowed
to receive PAH background therapy throughout the study, either PDE-5 inhibitors
or oral/inhaled prostanoids. The effect of macitentan on the endpoint was
observed irrespective of background therapy for pulmonary arterial hypertension.
The most commonly reported adverse drug reactions with Opsumit were
nasopharyngitis (14.0%), headache (13.6%) and anemia (13.2%).
MERIT, a randomized controlled study, was designed to assess the efficacy and
safety of macitentan in patients with inoperable chronic thromboembolic
pulmonary hypertension (CTEPH). In MERIT, 80 inoperable patients were randomized
to receive 10 mg of macitentan or placebo once daily over a 24 week treatment
period. After 16 weeks the treatment effect was a significant 16% reduction in
pulmonary vascular resistance (PVR) with macitentan compared with placebo (95%
CL: -30%, -1%; p=0.04 intention-to-treat (ITT)). The efficacy observed was
consistent across all sub-groups, included patients receiving background PH
specific therapy at baseline (61%), including PDE-5 inhibitors (59%). Mean PVR
decreased from baseline in both macitentan and placebo groups (geometric mean
percent ratios of Week 16/baseline 73.0% and 87.2%, respectively). The study
also showed a significant positive effect of macitentan compared to placebo on
exercise capacity. After 24 weeks of treatment, the mean change in 6-minute walk
distance (6-MWD) from baseline was an increase of 35 meters (m) in macitentan
and 1 m in placebo. The 6-MWD least-squares mean difference at Week 24 was 34.0
meters between macitentan and placebo (95% CL: 2.9, 65.2 m; p=0.03). Macitentan
was well tolerated in this patient population and safety was in general
consistent with the known safety profile for macitentan from previous clinical
studies. The most frequently reported adverse events that occurred with higher
frequency on macitentan vs. placebo were peripheral edema (22.5% vs. 10.0%) and
events related to anemia (17.5% vs. 2.5%). Hemoglobin decreases were observed in
both macitentan and placebo groups and in only one subject in each group
hemoglobin values decreased below 100 g/L during the study.
Macitentan is currently being further evaluated in multiple studies to expanding
the clinical utility of this important product in PAH and beyond.
ABOUT PULMONARY ARTERIAL HYPERTENSION (PAH)
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), prostacyclin receptor agonists, 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. Learn more
at http://www.pahuman.com/
Actelion Ltd.
Actelion Ltd. is a leading biopharmaceutical company focused on the discovery,
development and commercialization of innovative drugs for diseases with
significant unmet medical needs.
Actelion is a leader in the field of pulmonary arterial hypertension (PAH). Our
portfolio of PAH treatments covers the spectrum of disease, from WHO Functional
Class (FC) II through to FC IV, with oral, inhaled and intravenous medications.
Although not available in all countries, Actelion has treatments approved by
health authorities for a number of specialist diseases including Type 1 Gaucher
disease, Niemann-Pick type C disease, Digital Ulcers in patients suffering from
systemic sclerosis, and mycosis fungoides type cutaneous T-cell lymphoma.
Founded in late 1997, with now over 2,500 dedicated professionals covering all
key markets around the world including Europe, the US, Japan, China, Russia and
Mexico, Actelion has its corporate headquarters in Allschwil / Basel,
Switzerland.
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(®)). All
trademarks are legally protected.
For further information please contact:
Andrew Weiss
Senior Vice President, Head of Investor Relations & Corporate Communications
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
www.actelion.com
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may vary materially from those described herein as anticipated, believed,
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Source: Actelion Pharmaceuticals Ltd via GlobeNewswire
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