Actelion announces commercial availability of Uptravi (selexipag) in Germany

Market authorization for treatment of pulmonary arterial hypertension granted by European Commission on 12 May 2016
Uptravi available for patients in Germany as of 15 June 2016
FREIBURG, GERMANY and ALLSCHWIL, SWITZERLAND - 15 June 2016 - Actelion (SIX: ATLN) today announced the commercial availability of the oral, selective, IP prostacyclin receptor agonist, Uptravi® (selexipag) for the treatment of pulmonary arterial hypertension (PAH) in Germany.

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 mono therapy 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. [1]

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 selexipag in PAH patients with WHO Functional Class II-III, showing that selexipag was able to reduce the risk of a morbidity/mortality event by 40%. [2]

Professor H. Ardeschir Ghofrani, University Hospital Giessen, Germany, commented: "Uptravi offers an oral therapy that effectively targets the prostacyclin pathway and significantly delays the progression of pulmonary arterial hypertension. It is supported by robust outcome-based evidence in combination with an ERA, or a PDE-5 inhibitor, and even in combination with both an ERA and a PDE-5 inhibitor. This opens the way for more oral combination treatments early on in the progression of the disease, with proven long-term outcome benefits for more patients."

Michael Danzl, General Manager of Actelion Germany, commented: "The availability of Uptravi is a milestone for PAH patients in Germany, where until now, the options for treatments targeting the prostacyclin pathway have been limited, and were burdensome for the patients. With Uptravi, there is now an oral option in all three established treatment pathways."

Hans Dieter Kulla, President of pulmonale hypertonie e.v., added: "This new product launch is a major step in terms of achieving the best possible care for patients living with PAH in Germany. We hope Uptravi can further impact the long-term outcome for many patients, which ultimately also helps their families and caregivers."

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.

Uptravi is available in the following strengths: 200 mcg [Light yellow tablet debossed with 2], 400 mcg [Red tablet debossed with 4], 600 mcg [Light violet tablet debossed with 6], 800 mcg [Green tablet debossed with 8], 1000 mcg [Orange tablet debossed with 10], 1200 mcg [Dark violet tablet debossed with 12], 1400 mcg [Dark yellow tablet debossed with 14], 1600 mcg [Brown tablet debossed with 16]. Full prescribing information for healthcare professionals can be found on www.actelion.com

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NOTES TO EDITOR

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) [3-7]
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 [2]
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 [8]
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 H. ARDESCHIR GHOFRANI
H. Ardeschir Ghofrani, MD, received his medical degree from the Medical School at Giessen University in Germany. He is Professor of Internal Medicine at University Hospital Giessen and Marburg. He is currently Head of the Pulmonary Hypertension Division, Department of Internal Medicine, at Giessen. He also leads a collaborative group on cardiopulmonary vascular system research. He is a steering committee member of the Excellence Cluster Cardiopulmonary System, and of the Universities of Giessen and Marburg Lung Center, which is part of the German Center of Lung Research. In addition, he is Director of Pneumology at the Kerckhoff Heart and Lung Center in Bad NAuheim, Germany. Professor Ghofrani has participated in the therapeutic development of surfactants, prostanoids, PDE-5 inhibitors, combination therapies, soluble guanylate cyclase (sGC) activators/stimulators, endothelin receptor antagonists, and tyrosine kinase inhibitors. He has received numerous awards and is a reviewer for several journals, including theAmerican Journal of Respiratory and Critical Care Medicine, European Respiratory Journal, Circulation, and Lancet.

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

Uptravi summary of product characteristics (SmPC)
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
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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