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Actelion submits US FDA New Drug Application for selexipag (Uptravi) in patients with pulmonary arterial hypertension


December 23, 2014 - London

Actelion Pharmaceuticals Ltd /Actelion submits US FDA New Drug Application for selexipag (Uptravi) in patients with 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 2014 - Actelion Ltd (SIX: ATLN) today announced that it has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) seeking approval for selexipag (Uptravi®) for the treatment of patients with pulmonary arterial hypertension (PAH).

Selexipag, the first selective oral IP prostacyclin receptor agonist, was studied in the pivotal Phase III GRIPHON study in 1,156 patients with pulmonary arterial hypertension (PAH). As reported in June 2014, the study demonstrated that selexipag decreased the risk of a morbidity/mortality event versus placebo by 39% (p<0.0001). Efficacy observed was consistent across the key subgroups; age, gender, WHO Functional Class, PAH etiology and background PAH therapy. Patients were treated for up to 4.2 years. The overall tolerability profile of selexipag in GRIPHON was consistent with prostacyclin therapies. Adverse reactions occurring more frequently (>5%) on selexipag compared to placebo are headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing.

Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "Successfully submitting the selexipag NDA dossier to the FDA is another great milestone for us at Actelion, and a great way to mark the end of a remarkable year for us all. With the submission process underway for selexipag with both the FDA and EMA, I am looking forward to 2015 and to continuing to work with health authorities to move forward with these submissions in order to make selexipag available to the PAH community at the earliest opportunity."

 

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Notes to Editor:

PULMONARY ARTERIAL HYPERTENSION (PAH)

Pulmonary arterial hypertension (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.

In PAH, survival rates are unacceptably low and PAH remains incurable.

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 to predominate.

ABOUT SELEXIPAG

Selexipag, originally discovered and synthesized by Nippon Shinyaku, is a potent, orally available, selective IP prostacyclin receptor agonist.

Selexipag selectively targets the prostacyclin receptor (also called IP-receptor). The IP receptor is one of 5 types of prostanoid receptor. Prostacyclin activates the IP receptor inducing vasodilation and inhibiting proliferation of vascular smooth muscle cells. Selexipag, unlike prostacyclin analogs, is selective for the IP receptor over other prostanoid receptors. In preclinical models selective IP receptor agonism has shown to maintain efficacy and reduce the risk of side effects mediated by activation of other prostanoid receptors, such as EP1 and EP3 receptors. [1,2,3]

Selexipag was previously evaluated in a Phase II, 43-patient, placebo-controlled, double-blind study, where patients were randomized in a 3:1 ratio receiving selexipag or placebo on top of PDE-5 inhibitor and/or ERA [4]

REGULATORY STATUS OF SELEXIPAG

Submission of a centralized Marketing Authorisation Application (MAA) was made to the European Medicines Agency (EMA) for selexipag (Uptravi®) in the treatment of pulmonary arterial hypertension in December 2014. The application is now pending validation. Regulatory review is also ongoing in New Zealand.

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 pulmonary arterial hypertension.

The GRIPHON study was the largest outcome trial ever conducted in PAH, enrolling patients in 181 centers from 39 countries in North and Latin America, Europe, Asia-Pacific and Africa.

GRIPHON enrollment was completed in May 2013 with 1,156 patients and represents the largest randomized, controlled study in PAH patients. Patients received twice daily administration of selexipag or placebo and were also permitted to receive background therapy of endothelin receptor antagonist and/or a phosphodiesterase-5 inhibitor when on a stable dose for at least 3 months prior to enrollment. 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 of time to the first morbidity/mortality event for selexipag compared to placebo and to evaluate the safety of the selexipag in PAH patients. All morbidity and mortality events reported by the investigators were adjudicated by an independent Critical Event Committee blinded to the study treatment.  

DOSING IN GRIPHON

Uptitration of selexipag allows each patient's maintenance dose to be individualized based on tolerability. Dosing in GRIPHON was initiated at 200 micrograms (mcg) bid and increased in steps of 200 mcg twice daily up to a maximum of 1600 mcg twice daily.

ABOUT SAFETY AND TOLERABILITY IN GRIPHON

The most common adverse events in GRIPHON that occurred with higher frequency on selexipag than placebo were in-line with those known in prostacyclin therapies; headache, diarrhea, nausea, jaw pain, vomiting, pain in extremity, myalgia, nasopharyngitis and flushing.

The proportion of patients discontinuing treatment due to adverse events was 14 percent on selexipag and 7 percent on placebo.

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 pulmonary arterial hypertension (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.

References

  1. 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.
  2. Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.Morrison et al. Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function. J Pharmacol Exp Ther 2010;335:249-255.
  3. Morrison et al. Differential effects of selexipag and prostacyclin analogs in rat pulmonary artery. J Pharmacol Exp Ther 2012;343:547-555. 
  4. 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

 

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

 

The above information contains certain "forward-looking statements", relating to the company's business, which can be identified by the use of forward-looking terminology such as "estimates","believes", "expects", "may", "are expected to", "will", "will continue", "should", "would be", "seeks","pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions.Such statements include descriptions of the company's investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected.


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Source: Actelion Pharmaceuticals Ltd via Globenewswire

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