Actelion Pharmaceuticals Ltd / The New England Journal of Medicine publishes "Selexipag for the treatment of pulmonary arterial hypertension" . Processed and transmitted by NASDAQ OMX Corporate Solutions. The issuer is solely responsible for the content of this announcement.
ALLSCHWIL, SWITZERLAND - 23 December 2015 - Actelion (SIX: ATLN) announced today that the New England Journal of Medicine (NEJM) has published the results of the oral, selective IP prostacyclin receptor agonist, selexipag, in patients with pulmonary arterial hypertension (PAH) .
Olivier Sitbon, MD, and primary author of the NEJM paper commented: "Selexipag has the potential to improve PAH management, and the publication by the New England Journal of Medicine reflects the importance of our findings in the GRIPHON study. For the first time we see an effect on long-term outcome with an oral therapy that targets the prostacyclin pathway, a pathway that has for too long been underutilized in the treatment of PAH patients."
The NEJM paper presents the results of the GRIPHON study, a multicenter, Phase III study in which 1,156 patients, 79.6% of whom were already treated for PAH at baseline, received either placebo or selexipag for a median of 63.7 weeks and 70.7 weeks respectively. The patients' dose was adjusted weekly until the individualized maximum tolerated dose was achieved (ranging from 200 micrograms twice daily to 1,600 micrograms twice daily).
In GRIPHON, the risk of the primary composite endpoint of death from any cause or complication related to PAH up to the end of the treatment period was reduced by 40% (p<0.001) with selexipag compared to placebo. The treatment effect was driven by hospitalization and disease progression, which accounted for 81.9% of the primary endpoint events. The benefit of selexipag was consistent across pre-specified patient sub-groups such as PAH classification, WHO functional class and use of medication for PAH, which included patients receiving an ERA and a PDE-5 inhibitor at baseline (n = 376; 32.5%).
Gérald Simonneau, MD, and a senior author of the NEJM paper commented: "These data show that significant improvements in long-term outcomes can be achieved in a broad range of PAH patients by targeting the prostacyclin pathway with selexipag. Even better, the improvement is seen in patients already receiving combination therapy with an ERA and PDE-5 inhibitor, opening the door to triple oral combination therapy in PAH."
Vallerie McLaughlin, MD, and a senior author of the NEJM paper commented: "The long-term benefits we have seen in the GRIPHON study suggest that we now have effective oral therapies utilizing all three key PAH pathways, a development that could enhance PAH care for many patients."
The adverse events observed with selexipag were consistent with those typically observed for prostacyclin therapies, including headache, diarrhea, nausea, and jaw pain. These adverse events were typically mild to moderate in severity. Overall, 7.1% of placebo-treated patients and 14.3% of selexipag-treated patients prematurely discontinued treatment due to adverse events.
Jean-Paul Clozel, MD and Chief Executive Officer of Actelion commented: "I am very proud that Actelion has - for the second time - a new drug effective in a long-term outcome study in PAH, published in the New England Journal of Medicine. Selexipag was recently approved by the US FDA for the treatment of PAH to delay disease progression and reduce the risk of hospitalization for PAH, and is under review by other regulatory authorities around the world. Together with our partners at Nippon Shinyaku, we hope to see the very significant benefit of treatment with selexipag made available to the PAH community very soon. I would like to take this occasion to thank the patients and investigators who contributed to this ground-breaking study."
NOTES TO EDITOR:
ABOUT THE QUOTED AUTHORS
Olivier Sitbon, MD, PhD, is Professor of Respiratory Medicine at the South Paris University, and a consultant and specialist at the French Referral Centre for Pulmonary Hypertension, Department of Respiratory and Intensive Care Medicine, Bicêtre University Hospital in Le Kremlin-Bicêtre. He also leads the Team 2 "Clinical Research" of the INSERM Unit "Pulmonary Hypertension: Pathophysiology and Innovative Therapies". Professor Sitbon has conducted extensive research in PAH and is responsible for the French registry of patients with PAH. His investigational activities include clinical studies on factors associated with PAH, such as HIV infection and portopulmonary hypertension, prognostic factors in PAH and the development of new strategies for the treatment of PAH. He has authored numerous peer-reviewed articles on pulmonary hypertension and related topics, and is a reviewer for the American Journal of Respiratory and Critical Care Medicine, Circulation, European Respiratory Journal and Chest, amongst other scientific journals. Professor Sitbon is a consultant to Actelion and served as a Steering Committee member to the GRIPHON study.
Gérald Simonneau, MD, is Head of the Department of Pneumology, Groupe Hospitalier Paris-Sud, South Paris University, France. In addition, Professor Simonneau has been Director of the National Reference Centre for Severe Pulmonary Hypertension since 2004 and was President of the Working Group on Pulmonary Circulation of the European Society of Cardiology. He has published widely in the field of pulmonary hypertension, in high impact factor peer-reviewed journals including New England Journal of Medicine, Lancet, Annals of Internal Medicine and Circulation. Professor Simonneau is also Director of the team on clinical research in pulmonary hypertension (INSERM U999). Professor Simonneau was a Steering Committee member to the GRIPHON study and serves as a consultant to Actelion.
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.
ABOUT THE STUDY DATA PUBLISHED IN NEJM 
In this event-driven, Phase III study, 1,156 patients with pulmonary arterial hypertension were randomized to receive placebo or selexipag in individualized doses (maximum 1,600 micrograms twice daily). Stable use of an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, or both was allowed at enrollment. The primary outcome measure was a composite of death or complication related to PAH up to the end of treatment period.
A primary end point event occurred in 397 patients (41.6% placebo, 27.0% selexipag). The hazard ratio for selexipag versus placebo was 0.60 (99% CI, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of events. The effect of selexipag on the primary end point was similar in patients not receiving treatment and already receiving treatment for the disease, including a combination of two therapies.
ABOUT THE SAFETY AND TOLERABILITY PUBLISHED IN NEJM 
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. Adverse events associated with prostacyclin occurred more frequent during the dose-adjustment phase, where they were used to define the individualized maximum tolerated dose.
REGULATORY STATUS OF SELEXIPAG (UPTRAVI®)
In December 2014, Actelion submitted the registration dossier for selexipag to both the US FDA and Europe's EMA. In December 2015, the US FDA approved Uptravi (selexipag) for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. The review with the EMA is ongoing. Submission of the registration dossier to other Health Authorities continues with regulatory review underway in Australia, Canada, New Zealand, South Korea, Switzerland, and Taiwan.
ABOUT SELEXIPAG [2-7]
Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, oral, selective IP prostacyclin receptor agonist.
Selexipag 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. Selexipag is efficacious in preclinical disease models and has reduced potential for side effects mediated by activation of other prostanoid receptors, such as EP1 and EP3 receptors.
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 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 an endothelin receptor antagonist and/or a phosphodiesterase-5 inhibitor at baseline, 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 primary end-point events reported by the investigators were adjudicated by a three person independent Critical Event Committee blinded to the study treatment.
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 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.
- Sitbon O et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2015; 373:2522-33.
- 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.
- 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.
- 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.
- Morrison et al. Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function. J Pharmacol Exp Ther 2010;335:249-255.
- Morrison et al. Differential effects of selexipag and prostacyclin analogs in rat pulmonary artery. J Pharmacol Exp Ther 2012;343:547-555.
- 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.
- Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
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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.
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