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Actelion Pharmaceuticals Ltd: Selexipag meets primary endpoint in pivotal Phase III GRIPHON outcome study in patients with

  Actelion Pharmaceuticals Ltd: Selexipag meets primary endpoint in pivotal      Phase III GRIPHON outcome study in patients with pulmonary arterial                                  hypertension  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 statistical significance.  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.  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.  ABOUT SELEXIPAG  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[1] and EP[3] 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  [6]                                         ###    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  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 PROSTACYCLIN  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.    References  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     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  Dr. McLaughlin is a consultant to Actelion    NIPPON SHINYAKU  For further information on Nippon Shinyaku please visit:    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 Weiss Senior Vice President, Head of Investor Relations & Corporate Communications Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil +41 61 565 62 62    The above information contains certain "forward-looking statements",  relating  to  the  company's  business,   which  can  be  identified   by  the  use   of  forward-looking  terminology  such  as  "estimates",  "believes",  "expects",  "may", "are  expected  to", "will",  "will  continue", "should",  "would  be",  "seeks", "pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company's investment  and research  and development  programs and  anticipated  expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. 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