Actelion receives US FDA approval of Uptravi (selexipag) for the treatment of pulmonary arterial hypertension
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Actelion Pharmaceuticals Ltd /
Actelion receives US FDA approval of Uptravi (selexipag) for the treatment of
pulmonary arterial hypertension
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* Uptravi(®) approved for treatment of pulmonary arterial hypertension (PAH,
WHO Group 1) to delay disease progression and reduce the risk of
hospitalization for PAH
* Uptravi will be made available to patients in the US in early January 2016
* Uptravi will become a significant treatment option in PAH and complements
Actelion's portfolio with Opsumit(®) and Veletri(®)
ALLSCHWIL, SWITZERLAND - 22 December 2015 - Actelion (SIX: ATLN) announced today
that the United States Food and Drug Administration (FDA) has approved the use
of the orally active, selective IP prostacyclin receptor agonist Uptravi
(selexipag),originally discovered and synthesized by Nippon Shinyaku, for the
treatment of pulmonary arterial hypertension (PAH).
Uptravi is indicated for the treatment of pulmonary arterial hypertension (PAH,
WHO Group I) to delay disease progression and reduce the risk of hospitalization
for PAH.
Effectiveness was established in a long-term study in PAH patients with WHO
Functional Class II-III symptoms. Patients had idiopathic and heritable PAH
(58%), PAH associated with connective tissue disease (29%), PAH associated with
congenital heart disease with repaired shunts (10%).
Vallerie McLaughlin MD, Director of the Pulmonary Hypertension Program in the
Division of Cardiovascular Medicine at the University of Michigan, United
States, commented: "The prostacyclin pathway has long been recognized as a key
target in PAH treatment. However, until now, it has been underutilized. This is
in part due to the significant burden existing prostanoid treatments have placed
on the patients and on those supporting them. The approval of Uptravi with its
convincing long-term outcome results means that many more patients can benefit
from this pathway and be treated much earlier in the course of their disease."
Jean-Paul Clozel, MD and Chief Executive Officer of Actelion, commented:
"Today's FDA approval of Uptravi is another major landmark for Actelion.
Together with our partners at Nippon Shinyaku we are proud to be able to offer
an outstanding oral therapy targeting the prostacyclin pathway. The label for
Uptravi recognizes the improvement in long-term outcomes, including reducing the
risk of hospitalization for PAH regardless of whether patients received
background therapy including an ERA, a PDE-5 inhibitor, or - for the first time
ever in PAH - on top of a combination of both, an ERA and a PDE-5 inhibitor."
Jean-Paul Clozel concluded: "Uptravi will significantly expand the options to
delay disease progression after initiation of therapy with a baseline treatment
like Opsumit and well ahead of Veletri for the late disease stage. Actelion now
has an unparalleled portfolio of treatments across the continuum of care in PAH
that offer a combination of long term-efficacy, safety and convenience."
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.
Actelion expects Uptravi to become available to patients in the United States in
early January 2016. Outside of the United States, Actelion continues to work
with health authorities to obtain regulatory approval for Uptravi.
ABOUT THE GRIPHON STUDY DATA
The Uptravi approval was based in part on data from the long-term, global, Phase
III GRIPHON study in 1,156 patients treated for up to 4.2 years. The GRIPHON
study, in which more than 80% of patients were already receiving PAH-specific
therapies, showed that the risk of the primary composite endpoint was reduced by
40% (p<0.0001) with selexipag compared to placebo.
The benefit of selexipag was consistent across pre-specified patient subgroups
such as disease etiology, functional class and baseline PAH therapy, including
patients already receiving combination therapy with an ERA and a PDE-5
inhibitor.
Titrating selexipag to an individualized maintenance dose based on tolerability
was effective in achieving long-term outcome benefits across the tested dose
range. The 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. After titrating to the highest tolerated dose, the benefit was consistent
across the pre-specified low- (200, 400 mcg b.i.d), medium- (600, 800, 1'000 mcg
b.i.d) and high-maintenance (1'200, 1'400, 1'600 mcg b.i.d) dose groups.
###
NOTES TO EDITOR:
REGULATORY STATUS OF SELEXIPAG
In December 2014, Actelion submitted the registration dossier for selexipag to
both the US FDA and Europe's EMA, where review is ongoing. Submission of the
registration dossier to other Health Authorities is ongoing with regulatory
reviews underway in Australia, Canada, New Zealand, South Korea, Switzerland,
and Taiwan.
ABOUT UPTRAVI(®) (SELEXIPAG) [1-6]
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
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 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 [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 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 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 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.
ABOUT VALLERIE MCLAUGHLIN, MD
Vallerie V. McLaughlin, MD, is Director of the Pulmonary Hypertension (PH)
Program at the University of Michigan Health System and Professor of Internal
Medicine at the University of Michigan, Ann Arbor Mich. She is a Fellow of the
American College of Cardiology, the American College of Chest Physicians and the
American Heart Association, and is a member of the American Thoracic Society.
She has served as Chair of the American Heart Association "Women in Cardiology"
Committee, Chair of the Scientific Leadership Council of the PH Association,
Editor-in-Chief of Advances in Pulmonary Hypertension, Chair of the PH
Association Board of Trustees, and Chair of the Medical Education Programs of
the PH Association. She was Chair of the American College of Cardiology/American
Heart Association Clinical Expert Consensus Document on PH and has served on the
American College of Cardiology Scientific Sessions Program Committee. She was
inaugurated as a charter member into the Clinical Excellence Society at the
University of Michigan. Her research interests focus on PH. Professor McLaughlin
was a Steering Committee member to the GRIPHON study and serves as a consultant
to Actelion.
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. 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.
3. 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.
4. Morrison et al. Selexipag: a selective prostacyclin receptor agonist that
does not affect rat gastric function. J Pharmacol Exp Ther 2010;335:249-255.
5. Morrison et al. Differential effects of selexipag and prostacyclin analogs
in rat pulmonary artery. J Pharmacol Exp Ther 2012;343:547-555.
6. 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.
7. 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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