Actelion receives Health Canada approval for Uptravi (selexipag) for the long-term treatment of pulmonary arterial hypertension

ALLSCHWIL, SWITZERLAND - 26 January 2016 - Actelion (SIX: ATLN) announced today that Health Canada has granted a Notice of Compliance (NOC) approving the orally active, selective IP prostacyclin receptor agonist Uptravi (selexipag),originally discovered and synthesized by Nippon Shinyaku, for the treatment of pulmonary arterial hypertension.

Uptravi® is indicated for the long-term treatment of idiopathic pulmonary arterial hypertension (iPAH), heritable pulmonary arterial hypertension (HPAH), PAH associated with connective tissue disorders and PAH associated with congenital heart disease, in adult patients with WHO functional class (FC) II-III to delay disease progression. Disease progression included hospitalization for PAH, initiation of intravenous or subcutaneous prostanoids, or other disease progression events (decrease of 6-minute walk distance [6MWD] associated with either worsened PAH symptoms or need for additional PAH-specific treatment). Uptravi is effective in combination with an endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple combination with an ERA and a PDE-5 inhibitor, or as monotherapy.

Jean-Paul Clozel, MD and Chief Executive Officer of Actelion commented: "This approval represents a major milestone: the approval of a new oral medication that effectively targets the prostacyclin pathway. Uptravi is supported by robust long-term outcome results in combination with an ERA, or a PDE-5 inhibitor, and, for the first time in PAH, in triple combination with both an ERA and a PDE-5 inhibitor. We are now working diligently to make Uptravi available to patients in Canada as soon as possible, since we know how eagerly anticipated it is."

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

ABOUT THE GRIPHON STUDY DATA [1]

GRIPHON was a long-term, global Phase III study in 1,156 patients treated for up to 4.2 years. The GRIPHON study, in which more than 80% of patients were already receiving PAH-specific therapies, showed that the risk of the primary composite endpoint was reduced by 40% (p<0.0001) with selexipag compared to placebo.

The benefit of selexipag was consistent across pre-specified patient subgroups such as disease etiology, functional class and baseline PAH therapy, including patients already receiving combination therapy with an ERA and a PDE-5 inhibitor.

Titrating selexipag to an individualized maintenance dose based on tolerability was effective in achieving long-term outcome benefits across the tested dose range. The 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. or to the patient's individual highest tolerated dose. The benefit was consistent across the pre-specified low (200, 400 mcg b.i.d.), medium (600, 800, 1'000 mcg b.i.d.) and high maintenance (1'200, 1'400, 1'600 mcg b.i.d.) dose groups.

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NOTES TO EDITOR:

REGULATORY STATUS OF SELEXIPAG

In December 2014, Actelion submitted the registration dossier for selexipag to both the US FDA and Europe's EMA. Approval from the FDA was received on 21 December 2015, approval was also received from Health Canada on 21 January 2016. Submission of the registration dossier to other health authorities is ongoing, with regulatory reviews underway in Australia, Japan, New Zealand, South Korea, Switzerland, Taiwan and Turkey.

ABOUT UPTRAVI® (SELEXIPAG) [2-7]

Uptravi (selexipag), originally discovered and synthesized by Nippon Shinyaku, is a potent, oral, selective IP prostacyclin receptor agonist formulated as a tablet.

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.

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.

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.


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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