Actelion receives positive CHMP opinion for Uptravi (selexipag) for the long-term treatment of pulmonary arterial hypertension

ALLSCHWIL, SWITZERLAND - 29 January 2016 - Actelion (SIX: ATLN) announced today that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), issued a positive opinion for the use of the orally active, selective IP prostacyclin receptor agonist Uptravi (selexipag), originally discovered and synthesized by Nippon Shinyaku, for the treatment of pulmonary arterial hypertension.

The CHMP recommended that the European Commission approves Uptravi 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 CHMP's positive opinion is in part based on the review of efficacy and safety data generated in GRIPHON, a long-term Phase III study in PAH patients with WHO Functional Class I-IV symptoms. Patients were treated with Uptravi in combination with an ERA, a PDE-5 inhibitor, an ERA together with a PDE-5 inhibitor or as monotherapy. Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%) or PAH associated with congenital heart disease with repaired shunts (10%).

Marius Hoeper, a GRIPHON Steering Committee member, commented: "The prostacyclin pathway is one of the fundamental pathways to be targeted in PAH. However, it has been underutilized, mainly because of the significant burden that the route of administration of existing treatments places on patients and their caregivers. This positive opinion moves us a step closer to the EMA-approval of Uptravi (selexipag), with the promise of efficacious oral treatment, supported by excellent long-term outcome results, within reach."

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.

Jean-Paul Clozel, MD and Chief Executive Officer of Actelion, commented: "We are delighted by today's announcement of a positive CHMP opinion. Coming hot on the heels of both the US and Canadian approvals, we believe that Uptravi can significantly improve long-term outcomes for PAH patients. Once market authorization is granted by the EU Commission, Uptravi will open up the prostacyclin pathway to many more patients."

A CHMP positive opinion is one of the final steps before marketing authorization is granted by the European Commission. The European Commission is expected to issue a final decision by early April 2016.

ABOUT THE GRIPHON STUDY DATA

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. After titrating to each 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.

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.

ABOUT THE GRIPHON STUDY [1]

GRIPHON, (Prostacyclin (P G I ₂ ) R eceptor agonist In P ulmonary arterial H ypertensi ON ) 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 [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 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.

ABOUT MARIUS HOEPER

Marius M. Hoeper, MD, was educated at Hannover Medical School, where he specialized in respiratory medicine and intensive care medicine. In 1992, he received a two-year grant from Germany's National Research Foundation for a post-doc training at the University of Colorado, Denver, USA. After that training had been completed, Professor Hoeper moved back to Hannover Medical School, where he now holds the position of Senior Physician in the Department of Respiratory Medicine. He is in charge of the pulmonary hypertension program and attending physician of the medical intensive care unit. His main scientific interest lies in the field of pulmonary hypertension, where he has published more than 200 papers. In addition, Professor Hoeper serves as a regular reviewer for major medical journals in the field and is a member of the editorial board of the American Journal of Respiratory and Critical Care Medicine, as well as an associate editor with the European Respiratory Journal, senior editor with the Journal of Heart and Lung Transplantation and pulmonary hypertension section editor for The Journal of the American College of Cardiology (JACC).

Prof Hoeper has been a task force member at the 3rd World Symposium on Pulmonary Hypertension in Venice (2003), a task force chair at the 4th World Symposium on Pulmonary Hypertension in Dana Point (2008) and at the 5th World Symposium on Pulmonary Hypertension in Nice (2013). He has been an author and section editor of the 2009 European Guidelines for Pulmonary Hypertension. In addition, he is the senior author of the 2015 European Pulmonary Hypertension Guidelines. In 2014, Prof Hoeper received the distinguished Lifetime Achievement in Pulmonary Arterial Hypertension Award from the European Respiratory Society.

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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