Actelion's New Drug Application for selexipag (Uptravi) is accepted by the US FDA with a standard review time
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Actelion Pharmaceuticals Ltd /
Actelion's New Drug Application for selexipag (Uptravi) is accepted by the US
FDA with a standard review time
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ALLSCHWIL, SWITZERLAND - 03 March 2015 - Actelion Ltd (SIX: ATLN) today
announced the formal acceptance of the New Drug Application (NDA) for selexipag
(Uptravi(®)) by the US Food and Drug Administration (FDA).
The NDA dossier for selexipag (Uptravi) in the treatment of pulmonary arterial
hypertension (PAH) was submitted to the FDA on the 22(rd) December 2014.
Actelion expects results from the review process 12 months from the date of NDA
submission.
The FDA application for selexipag (Uptravi), the first selective oral
prostacyclin IP receptor agonist, is based on the findings of the positive
pivotal Phase III GRIPHON study in 1,156 patients with pulmonary arterial
hypertension (PAH).
The GRIPHON study demonstrated that selexipag decreased the risk of a
morbidity/mortality event versus placebo by 40% (p<0.0001). Efficacy observed
was consistent across the key subgroups: age, gender, WHO Functional Class, PAH
etiology and background PAH therapy. Patients were treated for up to 4.2 years.
The tolerability profile of selexipag in GRIPHON was consistent with
prostacyclin therapies. Adverse reactions occurring more frequently (>5%) on
selexipag compared to placebo are headache, diarrhea, jaw pain, nausea, myalgia,
vomiting, pain in extremity, and flushing.
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "The
acceptance of the Uptravi dossier by the FDA is great news, our team has put
considerable efforts into delivering a high quality dossier and this takes us
one step closer to offering a new treatment option to the PAH community. I am
looking forward to sharing our deep understanding of the data with health
authorities throughout 2015 and also with the broader scientific community,
starting with the first presentation at ACC in March."
The first scientific presentation of the data will take place at the 2015
American College of Cardiology congress (ACC.15) on Sunday March 15th in San
Diego, California.
###
Notes to Editor:
REGULATORY STATUS OF SELEXIPAG
In December 2014, Actelion submitted the registration dossier for selexipag to
both Europe's EMA and the US FDA for the treatment of patients with pulmonary
arterial hypertension. Submission of the registration dossier to other Health
Authorities is ongoing with regulatory review underway in New Zealand,
Switzerland and Canada.
ABOUT SELEXIPAG
Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a
potent, orally available, selective IP prostacyclin receptor agonist.
Selexipag selectively targets the prostacyclin receptor (also called IP-
receptor). The IP receptor is one of 5 types of prostanoid receptor.
Prostacyclin activates the IP receptor inducing vasodilation and inhibiting
proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin
analogs, is selective for the IP receptor over other prostanoid receptors. In
preclinical models selective IP receptor agonism has shown to maintain efficacy
and reduce the risk of side effects mediated by activation of other prostanoid
receptors, such as EP(1) and EP(3) receptors. [1,2,3]
Selexipag was previously evaluated in a Phase II, 43-patient, placebo-
controlled, double-blind study, where patients were randomized in a 3:1 ratio
receiving selexipag or placebo on top of PDE-5 inhibitor and/or ERA. [4]
ABOUT GRIPHON
GRIPHON, (Prostacyclin (PGI2) 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 pulmonary arterial hypertension.
The GRIPHON study was the largest outcome trial ever conducted in PAH, enrolling
patients in 181 centers from 39 countries in North and Latin America, Europe,
Asia-Pacific and Africa.
GRIPHON enrollment was completed in May 2013 with 1,156 patients and represents
the largest randomized, controlled study in PAH patients. Patients received
twice daily administration of selexipag or placebo and were also permitted to
receive background therapy of endothelin receptor antagonist and/or a
phosphodiesterase-5 inhibitor when on a stable dose for at least 3 months prior
to enrollment. 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 of
time to the first morbidity/mortality event for selexipag compared to placebo
and to evaluate the safety of the selexipag in PAH patients. All morbidity and
mortality events reported by the investigators were adjudicated by an
independent Critical Event Committee blinded to the study treatment.
DOSING IN GRIPHON
Uptitration of selexipag allows each patient's maintenance dose to be
individualized based on tolerability. Dosing in GRIPHON was initiated at 200
micrograms (mcg) bid and increased in steps of 200 mcg twice daily up to a
maximum of 1600 mcg twice daily.
ABOUT SAFETY AND TOLERABILITY IN GRIPHON
The most common adverse events in GRIPHON that occurred with higher frequency on
selexipag than placebo were in-line with those known in prostacyclin therapies;
headache, diarrhea, nausea, jaw pain, vomiting, pain in extremity, myalgia,
nasopharyngitis and flushing.
The proportion of patients discontinuing treatment due to adverse events was 14
percent on selexipag and 7 percent on placebo.
THE ROLE OF THE PROSTACYCLIN PATHWAY
The prostacyclin pathway is one of the 3 essential 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 to predominate.
PULMONARY ARTERIAL HYPERTENSION (PAH)
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), 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.
In PAH, survival rates are unacceptably low and PAH remains incurable.
ABOUT THE ACTELION / NIPPON SHINYAKU ALLIANCE
Actelion and Nippon Shinyaku entered into an exclusive worldwide alliance in
April 2008 to collaborate on selexipag, a first orally-available, selective
prostacyclin IP receptor agonist for patients suffering from pulmonary arterial
hypertension (PAH). This compound was originally discovered and synthesized by
Nippon Shinyaku. 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. 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.
2. Mubarak KK. A review of prostaglandin analogs in the management of patients
with pulmonary arterial hypertension. Respir Med 2010;104:9-21.Morrison et
al. Selexipag: a selective prostacyclin receptor agonist that does not
affect rat gastric function. J Pharmacol Exp Ther 2010;335:249-255.
3. Morrison et al. Differential effects of selexipag and prostacyclin analogs
in rat pulmonary artery. J Pharmacol Exp Ther 2012;343:547-555.
4. 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
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: 03.03.2015 - 17:35 Uhr
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