Press Releases / Notices

• ・Marketing authorization granted by European Commission on 12 May 2016
• ・First European Union (EU) market introduction to commence in the near future

ALLSCHWIL, SWITZERLAND – 17 May 2016 –  Actelion (SIX: ATLN) announced today that the European Commission has granted marketing authorization in the EU for the orally active, selective IP prostacyclin receptor agonist Uptravi^® (selexipag) for the treatment of pulmonary arterial hypertension.

 Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients with WHO functional class  (FC) II-III, either as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor, or as monotherapy in patients who are not candidates for these therapies. Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease.

 The EU label for Uptravi (originally discovered and synthesized by Nippon Shinyaku) was based in part on the Phase III GRIPHON study, whose main findings were published in the New England Journal of Medicine in December 2015. This placebo-controlled study, the largest ever in PAH, established the effectiveness, safety and tolerability of Uptravi in PAH patients with WHO Functional Class II-III. [1]

 In GRIPHON, the risk of a primary composite endpoint event, of complication related to PAH or death from any cause, 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 subgroups 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%).

 Professor Sean Gaine, Consultant Respiratory Physician at Mater Misericordiae Hospital Dublin, commented: “For many years we have known that the prostacyclin pathway can be key in treating PAH – yet due to the route of administration of the existing therapies being so burdensome, the pathway has been largely underused, with only about 20% of patients ever receiving a prostacyclin at some point during their PAH treatment. Uptravi, as an innovative oral treatment that is supported by long-term outcome results, now allows us to offer combination therapy regimens that target all three established treatment pathways.”

 Professor Nazzareno Galiè, Head of the Pulmonary Hypertension Center at the Institute of Cardiology, University of Bologna, added: “The approval of Uptravi is very positive news for the PAH community in Europe. With Uptravi, for the first time ever, we see a significant clinical benefit in combination with one and even two drugs targeting other treatment pathways. Together with its favorable tolerability profile, this makes Uptravi a treatment option that could truly change PAH care, for many patients.”

 Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion, commented: “Actelion has a comprehensive portfolio of treatments across the continuum of care in PAH that provide long-term outcome benefits. We are very pleased with today’s approval of Uptravi by the European Commission as it enables us to offer this outstanding oral medication, which provides long-term outcome benefits even for patients receiving background therapy, to PAH patients in Europe. We will now do our best to make Uptravi available to patients in the European Union as soon as possible.”

 The safety of selexipag has been evaluated in a long-term, Phase III placebo controlled study enrolling 1,156 patients with symptomatic PAH. The mean treatment duration was 76.4 weeks (median 70.7 weeks) for patients receiving selexipag versus 71.2 weeks (median 63.7 weeks) for patients on placebo. The exposure to selexipag was up to 4.2 years.

 The most commonly reported adverse reactions related to the pharmacological effects of Uptravi are headache, diarrhoea, nausea and vomiting, jaw pain, myalgia, pain in extremity, arthralgia, and flushing. These reactions are more frequent during the up-titration phase. The majority of these reactions are of mild to moderate intensity.

 The company will now work diligently to make Uptravi available throughout the European Union as soon as possible and start with the market introduction in Germany in the near future. In France, a cohort ATU for Uptravi has been approved, which has commenced for patients insufficiently controlled on an ERA/PDE-5 inhibitor combination therapy.

REGULATORY STATUS OF SELEXIPAG
 Market authorization has so far been received in the US (21 December 2015), Canada (21 January 2016), New Zealand (17 March 2016), Australia (18 March 2016), South Korea (11 May 2016) and the European Commission (12 May 2016). Submission of the registration dossier to other health authorities is ongoing, with regulatory reviews underway in Japan, Switzerland, Taiwan and Turkey.

ABOUT UPTRAVI^® (SELEXIPAG) [2-7]
 Uptravi (selexipag), originally discovered and synthesized by Nippon Shinyaku, is the only approved oral, selective IP receptor agonist targeting the prostacyclin pathway in PAH.
 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 [1]
 GRIPHON, a global, pivotal Phase III 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 selexipag in PAH patients.
 A total of 1’156 patients were randomized to receive placebo or selexipag. Utilizing a dosing scheme that titrated patients up to their individualized doses, 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. If patients were unable to tolerate a dose, the dose was reduced to the previously tolerated dose. A primary endpoint event occurred in 397 patients – 41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events.
 At baseline, almost 80% of patients were receiving oral medication specific for PAH: either an ERA, a PDE-5 inhibitor, or a combination of the two. The effect of selexipag with respect to the primary endpoint was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of both ERA and PDE-5 inhibitor).
 Adverse reactions occurring more frequently on Uptravi compared to placebo by ≥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 were more frequent during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of patients on selexipag and in none of the patients on placebo.

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 receptor agonists, 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. Learn more at http://www.pahuman.com/

ABOUT NAZZARENO GALIÈ
 Professor Nazzareno Galiè heads the Pulmonary Hypertension Centre at the Institute of Cardiology and is Associate Professor of Cardiology at the Medical Faculty of the University of Bologna, Italy. He also teaches at the Postgraduate Medical Schools of Cardiology, Pulmonary Diseases, and Rheumatology at the University of Bologna. He is Director of the international master's degree in pulmonary vascular diseases of the University of Bologna since 2007. He has authored over 136 scientific publications indexed in PubMed on heart failure, heart transplantation and pulmonary hypertension (h-index = 49). Professor Galiè is a Scholar of the Italian Society of Cardiology, Gold Medal recipient of the Polish Cardiac Society, Fellow of the European Society of Cardiology (ESC), and Honorary Fellow of the Royal College of Physicians, UK. He is past-Chairman of the Working Group on Pulmonary Circulation of the ESC and Co-Chairman of the Joint Task Force of the ESC and the European Respiratory Society for the guidelines on pulmonary hypertension.

ABOUT SEAN GAINE
 Professor Sean Gaine is Consultant Respiratory Physician at Mater Misericordiae Hospital in Dublin. He completed his residency and fellowship training at the Johns Hopkins Hospital, Baltimore, USA, and subsequently held faculty positions at the Johns Hopkins Hospital, and at the University of Maryland School of Medicine. He established the Pulmonary Hypertension Centre at the Johns Hopkins Hospital in 1999 and subsequently the National Pulmonary Hypertension Unit in Dublin. His research interests include new therapeutic agents for the management of pulmonary vascular diseases. Professor Gaine is a member of numerous international associations and is Fellow of the College of Chest Physicians, the Royal College of Physicians in Ireland and the Faculty of Sports and Exercise Medicine. He is Chief Medical Officer of the Olympic Council of Ireland and led the medical team at the Olympic Games in Athens, Beijing and London.

ABOUT THE ACTELION / NIPPON SHINYAKU ALLIANCE
 In April 2008, Actelion and Nippon Shinyaku entered into an exclusive worldwide alliance, under which 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. Sitbon O et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2015; 373:2522-33. 
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. 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.
4. 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.
5. Morrison et al. Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function. J Pharmacol Exp Ther 2010;335:249-255.
6. Morrison et al. Differential effects of selexipag and prostacyclin analogs in rat pulmonary artery. J Pharmacol Exp Ther 2012;343:547-555.
7. 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.
8. Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.