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ALLSCHWIL, SWITZERLAND - 24 April 2009 - Actelion Ltd (SIX: ATLN) announced today that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), issued a positive opinion for the pediatric formulation of bosentan (TracleerŪ) for the treatment of pulmonary arterial hypertension (PAH).
The CHMP recommended that the European Commission approves the new dispersible 32mg tablet formulation of bosentan, which was specifically developed for children, and which was studied in children with PAH down to the age of two years in the pediatric program. The European Commission is expected to make a final decision within two months. Actelion continues to work with authorities world-wide, including the US, to authorize the new dispersible formulation and to expand the PAH product information for bosentan bringing the treatment age down to 2 years of age.
Bosentan is an oral, dual endothelin receptor antagonist, which is already approved as TracleerŪ in Europe for the treatment of PAH; in WHO functional class III PAH to improve exercise capacity and symptoms and in PAH WHO Functional Class II where some improvements have also been shown [1]. In the EU, TracleerŪ is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.
PAH is a severe condition in children with an estimated median survival of 10 months, if left untreated, after diagnosis [2]. Currently, no drug is indicated for the treatment of PAH in children below 12 years of age; once licensed, bosentan will be the only PAH treatment with a pediatric formulation.
The pediatric program investigated the, pharmacokinetics, tolerability and safety of the new dispersible formulation of bosentan. The safety profile was consistent with that seen in the adult population.
The new, quadrisect, dispersible 32mg tablet formulation, specifically developed for children above the age of 2 years, allows for simple dose calculation and administration.
Notes to Editor:
About 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 function of the heart and lungs is severely compromised, manifested by a limited exercise capacity, and, ultimately, a reduced life expectancy. Approximately 100,000 people in Europe and the United States are afflicted with either primary or secondary forms of the disease related to conditions or tissue disorders that affect the lungs, such as scleroderma, lupus, HIV/AIDS or congenital heart disease.
PAH is associated with structural changes in both the pulmonary vasculature and the right ventricle. Recent advances [4] in the understanding of the pathogenic factors leading to the pulmonary vascular disease have led to the development of new therapies targeting specific pathways (the prostacyclin pathway; the endothelin pathway; and the nitric oxide pathway) [5]. The available therapies have positive effects in PAH, but they do not provide a cure, and in many patients the disease will progress. PAH remains a serious life-threatening condition [5,6]. Early recognition and an understanding of the selection and timing of therapeutic options remain critical elements in the optimal management of patients with this disorder.
About PAH in Children
PAH is a severe condition in children with an estimated median survival of 10 months after diagnosis, if left untreated [2].
Online information on PAH is available at www.pah-info.com. PAH-info.com is part of an international PAH awareness campaign supported by Actelion Pharmaceuticals and has been created to provide information to healthcare professionals and patients.
About TracleerŪ in Pulmonary Arterial Hypertension (PAH)
TracleerŪ (bosentan), the first oral dual endothelin receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH) and made available by Actelion subsidiaries in the United States, the European Union, Japan, Australia, Canada, Switzerland and other markets worldwide.
Requires attention to two significant safety concerns: Potential for serious liver injury (including rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring) - Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter. TracleerŪ treatment must not be initiated in women of childbearing potential unless they practice reliable contraception and participate in monthly pregnancy testing. Due to these risks, TracleerŪ is only supplied through a controlled distribution.
About FUTURE-1
Pediatric FormUlation of bosenTan in pUlmonary arterial hypertension (FUTURE-1) was an open-label, multicenter, non-controlled, pharmacokinetic, safety and tolerability Phase III study. A new oral, dispersible, quadrisected formulation of bosentan dedicated to pediatric patients was investigated; patients received 2 mg/kg bid for 4 weeks then 4 mg/kg bid until Week 12. The trial enrolled 36 patients aged ģ2 and <12 years with idiopathic PAH or familial PAH.
The main objective was to demonstrate that exposure to the pediatric formulation of bosentan in children with PAH is similar to the known exposure of the adult formulation. The primary study endpoint was AUCtau of bosentan, determined at Week 12. Secondary objectives included evaluation of tolerability and safety of bosentan in pediatric patients with PAH. Secondary endpoints were safety parameters and the additional pharmacokinetic parameters of Cmax and Tmax. Exploratory endpoints included: changes from baseline to Week 12 in health-related quality of life, WHO functional class, and Global Clinical Impression.
In FUTURE-1, the observed exposure to bosentan was similar to that in children who participated in BREATHE-3 (who received the adult formulation of bosentan). A subset of 11 patients had pharmacokinetics evaluated after receiving both 2 and 4 mg/kg doses. In these patients, exposure to bosentan was comparable at both doses: geometric mean AUCtau was 3577 ng x h/mL and 3371 ng x h/mL with bosentan 2 mg/kg and 4 mg/kg, respectively, and geometric mean Cmax was 583 ng/mL and 649 ng/mL, respectively.
The safety and tolerability profile of bosentan was consistent with that observed in previous placebo-controlled clinical trials in the adult population.
An open-label safety extension, FUTURE-2, is ongoing to assess long-term safety and outcome data.
About TracleerŪ in Digital Ulcers (DU)
DUs are a manifestation of the underlying vasculopathy which is central to the pathophysiology of systemic sclerosis (SSc) and pivotal in the development of PAH in SSc, one of the leading causes of death in SSc. Endothelin, a pathogenic mediator, is implicated in the underlying vasculopathy in SSc.
DUs can be a frequent, persistent and debilitating complication of SSc. They are caused by a reduction in the lumen of small bloody vessels that decreases blood flow to the fingers and toes causing open sores. DUs are painful, with a debilitating impact on patients' daily life, often making it impossible to work and undertake even simple day-to-day activities, particularly those associated with fingertip function. Reducing the occurrence of new DUs is an important and achievable treatment goal in SSc.
In the EU, TracleerŪ is indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. TracleerŪ has been shown to improve hand function (i.e. dressing and hygiene) in patients with scleroderma-induced digital ulcers.
Requires attention to two significant safety concerns [1]: Potential for serious liver injury (including rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring) - Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter. High potential for major birth defects - Pregnancy must be excluded and prevented by two forms of birth control; monthly pregnancy tests should be obtained. Because of these risks, TracleerŪ is only supplied through controlled distribution.
References
TracleerŪ SmPC.
D'Alonzo G et al. Survival in patients with primary pulmonary hypertension. Annals of Internal Medicine 1991; 115:343-349.
Sitbon O et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111: 3105-3111.
Farber HW; Loscalzo J. Mechanisms of disease: pulmonary arterial hypertension. N. Eng. J. Med. 2004; 351:1655-65.
Humbert M; Sitbon O; Simonneau G. Treatment of pulmonary arterial hypertension. N. Eng. J. Med. 2004;351:1425-36.
Humbert M; Morrell NW; Archer SL; et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2004; 43: Suppl. 12: 13S-24S.
Actelion Ltd
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug TracleerŪ, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets TracleerŪ through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium - the single layer of cells separating every blood vessel from the blood stream. Actelion's over 2000 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMIŪ).
For further information please contact:
Medical Media Contact
Elizabeth Perry
Packer Forbes
+44 208 772 1551
elizabeth@packerforbes.com
Investor Contact
Roland Haefeli
Vice President, Head of Investor Relations & Public Affairs
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
+1 650 624 69 36
http://www.actelion.com
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