Actelion Pharmaceuticals Ltd: Selexipag meets primary endpoint in pivotal
Phase III GRIPHON outcome study in patients with pulmonary arterial
Actelion Pharmaceuticals Ltd / Selexipag meets primary endpoint in pivotal
Phase III GRIPHON outcome study in patients with pulmonary arterial
hypertension . Processed and transmitted by NASDAQ OMX Corporate Solutions.
The issuer is solely responsible for the content of this announcement.
ALLSCHWIL, SWITZERLAND - 16 June 2014 - Actelion Ltd (SIX: ATLN) today
announced the top-line results of the pivotal Phase III GRIPHON study in 1,156
patients with pulmonary arterial hypertension (PAH) with selexipag, the first
selective oral prostacyclin IP receptor agonist. Initial analysis shows that
the event-driven outcome study has met its primary efficacy endpoint with high
Selexipag decreased the risk of a morbidity/mortality event versus placebo by
39% (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 4.3 years. The overall tolerability profile of
selexipag in GRIPHON was consistent with prostacyclin therapies.
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "I
am overwhelmed by the result of this long-term outcome study that evaluated
selexipag in a setting where 80 percent of patients already received oral PAH
therapy at baseline. Together with our partner Nippon Shinyaku, we are now one
step closer to bringing an effective oral therapy targeting the prostacyclin
pathway to the PAH community. We will now work diligently to complete the
analyses with the goal to initiate first regulatory filings with Health
Authorities as soon as possible."
Gérald Simonneau, M.D., Professor of Pulmonology and Head of the Department of
Pulmonary Disease and Intensive Care Unit, Université Paris-Sud, Le
Kremlin-Bicêtre, France and Steering Committee member commented: "I have been
prescribing intravenous prostacyclin therapies in PAH patients for almost
twenty years. Today's GRIPHON results represent a major step forward. For the
first time, with selexipag, we have an oral compound acting on the
prostacyclin pathway showing a significant risk reduction on a highly
clinically relevant endpoint."
Guy Braunstein, M.D. and Head of Global Clinical Development commented: "I
would like to thank the PAH community for their long-term commitment, which
made this, the second morbidity/mortality outcome study from Actelion
possible. While we are just beginning to analyze the data, the top-line
results we have in hand today are already impressive. The concept of
individualized uptitration of selexipag according to tolerability was
successful, with a consistent result seen across the entire dose range."
Vallerie McLaughlin M.D., Director of the Pulmonary Hypertension Program in
the Divisionof Cardiovascular Medicine at the University of Michigan, United
States and Steering Committee member commented: "The GRIPHON study results
hold the promise that selexipag might open up the prostacyclin pathway to
different groups of patients given the consistent efficacy findings across key
subgroups evaluated in this long-term outcome study. In addition, GRIPHON has
shown once again that registration studies that follow the robust
morbidity/mortality definitions - as recommended by the 4^th and 5^th World
symposia on Pulmonary Hypertension - have the potential to deliver truly
meaningful clinical information."
Detailed study results will be made available through scientific disclosure at
upcoming congresses and in peer reviewed publications.
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 THE 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.
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.
Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a
potent, orally available, selective prostacyclin IP 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 and EP receptors. [2,4,5]
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
Notes to Editor:
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
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.
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.
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.
1.Kuwano et al. NS-304, an orally available and long-acting prostacyclin
receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
2.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.
3.Mubarak KK. A review of prostaglandin analogs in the management of
patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
4.Morrison et al. Selexipag: a selective prostacyclin receptor agonist that
does not affect rat gastric function. J Pharmacol Exp Ther
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
Dr. McLaughlin is a consultant to Actelion
For further information on Nippon Shinyaku please visit:
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,
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:
Senior Vice President, Head of Investor Relations & Corporate Communications
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
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