Actelion announces commercial availability of Uptravi (selexipag) in Germany
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Actelion Pharmaceuticals Ltd /
Actelion announces commercial availability of Uptravi (selexipag) in Germany
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* Market authorization for treatment of pulmonary arterial hypertension
granted by European Commission on 12 May 2016
* Uptravi available for patients in Germany as of 15 June 2016
FREIBURG, GERMANY and ALLSCHWIL, SWITZERLAND - 15 June 2016 - Actelion (SIX:
ATLN) today announced the commercial availability of the oral, selective, IP
prostacyclin receptor agonist, Uptravi(®) (selexipag) for the treatment of
pulmonary arterial hypertension (PAH) in Germany.
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 mono therapy 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. [1]
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 selexipag in PAH patients with WHO
Functional Class II-III, showing that selexipag was able to reduce the risk of a
morbidity/mortality event by 40%. [2]
Professor H. Ardeschir Ghofrani, University Hospital Giessen, Germany,
commented: "Uptravi offers an oral therapy that effectively targets the
prostacyclin pathway and significantly delays the progression of pulmonary
arterial hypertension. It is supported by robust outcome-based evidence in
combination with an ERA, or a PDE-5 inhibitor, and even in combination with both
an ERA and a PDE-5 inhibitor. This opens the way for more oral combination
treatments early on in the progression of the disease, with proven long-term
outcome benefits for more patients."
Michael Danzl, General Manager of Actelion Germany, commented: "The availability
of Uptravi is a milestone for PAH patients in Germany, where until now, the
options for treatments targeting the prostacyclin pathway have been limited, and
were burdensome for the patients. With Uptravi, there is now an oral option in
all three established treatment pathways."
Hans Dieter Kulla, President of pulmonale hypertonie e.v., added: "This new
product launch is a major step in terms of achieving the best possible care for
patients living with PAH in Germany. We hope Uptravi can further impact the
long-term outcome for many patients, which ultimately also helps their families
and caregivers."
The safety of Uptravi has been evaluated in a long-term, placebo-controlled
study enrolling 1,156 patients with symptomatic PAH (GRIPHON study). The
exposure to Uptravi in this trial was up to 4.2 years with median duration of
exposure of 1.4 years. Adverse reactions occurring more frequently on Uptravi
compared to placebo - greater than or equal to 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 are more frequent during the dose titration phase.
Hyperthyroidism was observed in 1% (n=8) of patients on Uptravi and in none of
the patients on placebo.
Uptravi is available in the following strengths: 200 mcg [Light yellow tablet
debossed with 2], 400 mcg [Red tablet debossed with 4], 600 mcg [Light violet
tablet debossed with 6], 800 mcg [Green tablet debossed with 8], 1000 mcg
[Orange tablet debossed with 10], 1200 mcg [Dark violet tablet debossed with
12], 1400 mcg [Dark yellow tablet debossed with 14], 1600 mcg [Brown tablet
debossed with 16]. Full prescribing information for healthcare professionals can
be found on www.actelion.com
###
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(®) (SELEXIPAG) [3-7]
Uptravi (selexipag), originally discovered and synthesized by Nippon Shinyaku,
is a potent, oral, selective IP prostacyclin receptor agonist.
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 [2]
GRIPHON, (Prostacyclin (PGI(2)) Receptor agonist In Pulmonary arterial
HypertensiON) was a randomized, multicenter, double-blind, placebo-controlled
trial evaluating the long-term efficacy and safety of oral selexipag in patients
with PAH.
The GRIPHON study was the largest randomized, controlled, outcome trial ever
conducted in PAH patient population, enrolling 1,156 patients in 181 centers
from 39 countries in North and Latin America, Europe, and Asia-Pacific. Patients
received twice daily administration of selexipag or placebo and were also
permitted to receive background PAH-specific therapy of an endothelin receptor
antagonist and/or a phosphodiesterase-5 inhibitor when on a stable dose for at
least 3 months. At baseline, 80% of patients were receiving oral medication
specific for PAH: either an ERA, a PDE-5 inhibitor, or a combination of the two.
This pivotal, event-driven study was designed to demonstrate a prolongation in
time to the first morbidity or mortality event for selexipag compared to placebo
and to evaluate the safety profile of selexipag in PAH patients. All morbidity
and mortality events reported by the investigators were adjudicated by a three
person independent Critical Event Committee blinded to the study treatment.
ABOUT THE SAFETY AND TOLERABILITY IN GRIPHON
Overall, 41 (7.1%) patients in the placebo group and 82 (14.3%) in the selexipag
group prematurely discontinued treatment due to an adverse event. The most
frequent adverse events leading to treatment discontinuation in the selexipag
group (>1% difference between selexipag and placebo) were headache (3.3%),
diarrhea (2.3%), and nausea (1.7%). Hyperthyroidism occurred in eight selexipag-
treated patients and led to treatment discontinuation in one patient. No serious
adverse events were reported more frequently (>1% difference between selexipag
and placebo) in the selexipag group. Prostacyclin-associated adverse events were
more frequent during the titration phase, where they were used to define the
individualized highest tolerated dose.
THE ROLE OF THE PROSTACYCLIN PATHWAY [8]
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 analogs 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.
ABOUT H. ARDESCHIR GHOFRANI
H. Ardeschir Ghofrani, MD, received his medical degree from the Medical School
at Giessen University in Germany. He is Professor of Internal Medicine at
University Hospital Giessen and Marburg. He is currently Head of the Pulmonary
Hypertension Division, Department of Internal Medicine, at Giessen. He also
leads a collaborative group on cardiopulmonary vascular system research. He is a
steering committee member of the Excellence Cluster Cardiopulmonary System, and
of the Universities of Giessen and Marburg Lung Center, which is part of the
German Center of Lung Research. In addition, he is Director of Pneumology at the
Kerckhoff Heart and Lung Center in Bad NAuheim, Germany. Professor Ghofrani has
participated in the therapeutic development of surfactants, prostanoids, PDE-5
inhibitors, combination therapies, soluble guanylate cyclase (sGC)
activators/stimulators, endothelin receptor antagonists, and tyrosine kinase
inhibitors. He has received numerous awards and is a reviewer for several
journals, including the American Journal of Respiratory and Critical Care
Medicine, European Respiratory Journal, Circulation, and Lancet.
ABOUT THE ACTELION / NIPPON SHINYAKU ALLIANCE
In April 2008, Actelion and Nippon Shinyaku entered into an exclusive worldwide
alliance, under which Actelion is responsible for global development and
commercialization of selexipag outside Japan, while the two companies will co-
develop and co-commercialize in Japan. Nippon Shinyaku will receive milestone
payments based on development stage and sales milestones as well as royalties on
any sales of selexipag.
References
1. Uptravi summary of product characteristics (SmPC)
2. Sitbon O et al. Selexipag for the Treatment of Pulmonary Arterial
Hypertension. N Engl J Med 2015; 373:2522-33.
3. Kuwano et al. A long-acting and highly selective prostacyclin receptor
agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique
relaxant responses of its active form MRE-269 on rat pulmonary artery. J
Pharmacol Exp Ther 2008;326:691-699.
4. Kuwano K et al. 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-
(methylsulfonyl)acetamide (NS-304), an orally available and long-acting
prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther
2007;322(3):1181-1188.
5. Tetsuo Asaki et al. Selexipag: an oral and selective IP prostacyclin
receptor agonist for the treatment of pulmonary arterial hypertension. J.
Med. Chem., Just Accepted Manuscript. DOI: 10.1021/acs.jmedchem.5b00698.
Web: 20 Aug 2015.
6. Morrison et al. Selexipag: a selective prostacyclin receptor agonist that
does not affect rat gastric function. J Pharmacol Exp Ther 2010;335:249-255.
7. Morrison et al. Differential effects of selexipag and prostacyclin analogs
in rat pulmonary artery. J Pharmacol Exp Ther 2012;343:547-555.
8. Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N.
Selexipag, an oral, selective IP receptor agonist for the treatment of
pulmonary arterial hypertension Eur Respir J 2012; 40: 874-880
9. Mubarak KK. A review of prostaglandin analogs in the management of patients
with pulmonary arterial hypertension. Respir Med 2010;104:9-21
NIPPON SHINYAKU
For further information on Nippon Shinyaku please visit:
http://www.nippon-shinyaku.co.jp/english/index.html
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 2,400 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 C. Weiss
Senior Vice President, Head of Investor Relations & Corporate Communications
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
http://www.actelion.com
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Datum: 15.06.2016 - 07:00 Uhr
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