Actelion Pharmaceuticals Ltd / Actelion is granted marketing
authorization for Uptravi (selexipag) in pulmonary arterial 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
future
ALLSCHWIL, SWITZERLAND - 17 May 2016 - 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(R) (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.
###
NOTES TO EDITOR:
REGULATORY STATUS OF SELEXIPAG
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 Turkey.
ABOUT UPTRAVI(R) (SELEXIPAG) [2-7]
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.
ABOUT THE GRIPHON STUDY [1]
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 ROLE OF THE PROSTACYCLIN PATHWAY [7]
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 predominate.
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
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