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Actelion Pharmaceuticals Ltd: Actelion is granted marketing authorization for Uptravi (selexipag) in pulmonary arterial hypertension by the European Commission

Actelion Pharmaceuticals Ltd / Actelion is granted marketing authorization for
Uptravi (selexipag) in pulmonaryarterial hypertension by the European
Commission . Processed and transmitted by NASDAQ OMX Corporate Solutions.The
issuer is solely responsible for the content of this announcement.
* Marketing authorization granted by European Commission on 12 May 2016
* First European Union (EU) market introduction to commence in the near

Actelion (SIX: ATLN) announced today that the European Commission has granted
marketing authorization in the EU for the orally active, selective IP
prostacyclin receptor agonist Uptravi®(selexipag) for the treatment of
pulmonary arterial hypertension.

Uptravi is indicated for the long-term treatment of pulmonary arterial
hypertension (PAH) in adult patients with WHO functional class (FC) II-III,
either as combination therapy in patients insufficiently controlled with an
endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5
(PDE-5) inhibitor, or as monotherapy in patients who are not candidates for
these therapies. 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.

The EU label for Uptravi (originally discovered and synthesized by Nippon
Shinyaku) was based in part on the Phase III GRIPHON study, whose main
findings were published in the New England Journal of Medicine in December
2015. This placebo-controlled study, the largest ever in PAH, established the
effectiveness, safety and tolerability of Uptravi in PAH patients with WHO
Functional Class II-III. [1]

In GRIPHON, the risk of a primary composite endpoint event, of complication
related to PAH or death from any cause, up to the end of the treatment
period, was reduced by 40% (p<0.001) with selexipag compared to placebo. The
treatment effect was driven by hospitalization and disease progression, which
accounted for 81.9% of the primary endpoint events. The benefit of selexipag
was consistent across pre-specified patient subgroups such as PAH
classification, WHO functional class and use of medication for PAH, which
included patients receiving an ERA and a PDE-5 inhibitor at baseline (n =
376; 32.5%).
Professor Sean Gaine, Consultant Respiratory Physician at Mater Misericordiae
Hospital Dublin, commented: "For many years we have known that the
prostacyclin pathway can be key in treating PAH - yet due to the route of
administration of the existing therapies being so burdensome, the pathway has
been largely underused, with only about 20% of patients ever receiving a
prostacyclin at some point during their PAH treatment. Uptravi, as an
innovative oral treatment that is supported by long-term outcome results, now
allows us to offer combination therapy regimens that target all three
established treatment pathways."

Professor Nazzareno Galiè, Head of the Pulmonary Hypertension Center at the
Institute of Cardiology, University of Bologna, added: "The approval of
Uptravi is very positive news for the PAH community in Europe. With Uptravi,
for the first time ever, we see a significant clinical benefit in combination
with one and even two drugs targeting other treatment pathways. Together with
its favorable tolerability profile, this makes Uptravi a treatment option
that could truly change PAH care, for many patients."

Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion, commented:
"Actelion has a comprehensive portfolio of treatments across the continuum of
care in PAH that provide long-term outcome benefits. We are very pleased with
today's approval of Uptravi by the European Commission as it enables us to
offer this outstanding oral medication, which provides long-term outcome
benefits even for patients receiving background therapy, to PAH patients in
Europe. We will now do our best to make Uptravi available to patients in the
European Union as soon as possible."

The safety of selexipag has been evaluated in a long-term, Phase III placebo
controlled study enrolling 1,156 patients with symptomatic PAH. The mean
treatment duration was 76.4 weeks (median 70.7 weeks) for patients receiving
selexipag versus 71.2 weeks (median 63.7 weeks) for patients on placebo. The
exposure to selexipag was up to 4.2 years.

The most commonly reported adverse reactions related to the pharmacological
effects of Uptravi are headache, diarrhoea, nausea and vomiting, jaw pain,
myalgia, pain in extremity, arthralgia, and flushing. These reactions are
more frequent during the up-titration phase. The majority of these reactions
are of mild to moderate intensity.

The company will now work diligently to make Uptravi available throughout the
European Union as soon as possible and start with the market introduction in
Germany in the near future. In France, a cohort ATU for Uptravi has been
approved, which has commenced for patients insufficiently controlled on an
ERA/PDE-5 inhibitor combination therapy.




Market authorization has so far been received in the US (21 December 2015),
Canada (21 January 2016), New Zealand (17 March 2016), Australia (18 March
2016), South Korea (11 May 2016) and the European Commission (12 May 2016).
Submission of the registration dossier to other health authorities is
ongoing, with regulatory reviews underway in Japan, Switzerland, Taiwan and


Uptravi (selexipag), originally discovered and synthesized by Nippon Shinyaku,
is the only approved oral, selective IP receptor agonist targeting the
prostacyclin pathway in PAH.

Uptravi and its major metabolite selectively target the prostacyclin receptor
(also called IP receptor). The IP receptor is one of 5 major types of
prostanoid receptor (IP, EP, DP, TP, FP). Prostacyclin activates the IP
receptor to induce vasodilation and inhibit proliferation of vascular smooth
muscle cells.


GRIPHON, a global, pivotal Phase III study, was designed to demonstrate a
prolongation of time to the first morbidity/mortality event for selexipag
compared to placebo and to evaluate the safety of selexipag in PAH patients.

A total of 1'156 patients were randomized to receive placebo or selexipag.
Utilizing a dosing scheme that titrated patients up to their individualized
doses, dosing in GRIPHON was initiated at 200 micrograms (mcg) twice daily
(b.i.d) and increased weekly in steps of 200 mcg up to a maximum of 1600 mcg
b.i.d. If patients were unable to tolerate a dose, the dose was reduced to
the previously tolerated dose. A primary endpoint event occurred in 397
patients - 41.6% of those in the placebo group and 27.0% of those in the
selexipag group (hazard ratio in the selexipag group as compared with the
placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease
progression and hospitalization accounted for 81.9% of the events.

At baseline, almost 80% of patients were receiving oral medication specific
for PAH: either an ERA, a PDE-5 inhibitor, or a combination of the two. The
effect of selexipag with respect to the primary endpoint was similar in the
subgroup of patients who were not receiving treatment for the disease at
baseline and in the subgroup of patients who were already receiving treatment
at baseline (including those who were receiving a combination of both ERA and
PDE-5 inhibitor).

Adverse reactions occurring more frequently on Uptravi compared to placebo
by>=3%, over the course of the study, were headache, diarrhea, jaw pain,
nausea, myalgia, vomiting, pain in extremity, flushing, arthralgia, anemia,
decreased appetite and rash. These adverse reactions were more frequent
during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of
patients on selexipag and in none of the patients on placebo.


The prostacyclin pathway is one of the 3 best characterized pathways involved
in the pathophysiology and treatment of PAH. Prostacyclin is a prostanoid and
serves as a signaling molecule in the human body. It is produced, like other
vasoactive substances, by endothelial cells. Prostacyclin induces
vasodilation, is anti-proliferative, has anti-inflammatory effects and
inhibits platelet aggregation. In certain disease conditions, the production
of prostacyclin by the endothelium is impaired, allowing for example, the
deleterious effects of excessive levels of endothelin or thromboxane to


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

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


Professor Nazzareno Galiè heads the Pulmonary Hypertension Centre at the
Institute of Cardiology and is Associate Professor of Cardiology at the
Medical Faculty of the University of Bologna, Italy. He also teaches at the
Postgraduate Medical Schools of Cardiology, Pulmonary Diseases, and
Rheumatology at the University of Bologna. He is Director of the
international master's degree in pulmonary vascular diseases of the
University of Bologna since 2007. He has authored over 136 scientific
publications indexed in PubMed on heart failure, heart transplantation and
pulmonary hypertension (h
-index = 49). Professor Galiè is a Scholar of the Italian Society of
Cardiology, Gold Medal recipient of the Polish Cardiac Society, Fellow of the

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