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Actelion Pharmaceuticals Ltd (OTC:ALIOF) Corporate news announcement processed and transmitted by Hugin ASA. The issuer is solely responsible for the content of this announcement. ---------------------------------------------------------------------- -------------- ALLSCHWIL, SWITZERLAND - 27 June 2008 - Actelion Ltd (SWX: 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 bosentan (Tracleer®) to extend its use in Pulmonary Arterial Hypertension (PAH).
The CHMP recommended that the European Commission approve bosentan (Tracleer®) for the treatment of PAH in WHO Functional Class II (FC II) patients based on the EARLY study results. The extension of the indication recommended by CHMP reads: "Some improvements have also been shown in patients with PAH WHO functional class II (see section 5.1)." The European Commission decision is expected within the next 2-3 months.
Tracleer® is an oral dual endothelin receptor antagonist, which is currently licensed for the treatment of PAH; in Europe in PAH FC III to improve exercise capacity and symptoms and in the United States in PAH FC III and IV to improve exercise capacity and decrease the rate of clinical worsening.1 Actelion is working with authorities in the US and in other countries worldwide to expand the label for Tracleer® to include WHO FC II. In the EU, Tracleer® is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.
There are four WHO functional classes for PAH with class I being the least severe and class IV being the most advanced. These reflect the impact on a patient's life in terms of symptoms and physical activity. FC II patients are defined as patients with PAH resulting in slight limitation of physical activity, they are comfortable at rest and ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope2.
Despite being mildly symptomatic, PAH patients in WHO functional class II suffer from a severe disease. EARLY (Endothelin Antagonist tRial in miLdlY symptomatic PAH patients), the only randomized controlled trial to exclusively study FC II patients, highlights rapid progression of PAH, regardless of symptoms and shows the benefit of treating these patients with Tracleer®. The study was recently published in "The Lancet" 3. ###
Notes to the Editor
About Pulmonary Arterial Hypertension (PAH) PAH is a syndrome characterized by a progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular failure and premature death.4 If untreated, PAH carries a very poor prognosis with a median survival of 2.8 years after diagnosis.5
There are four WHO functional classes for PAH with class I being the least severe and class IV being the most advanced. These reflect the impact on a patient's life in terms of symptoms and physical activity. Class II patients are defined as patients with pulmonary hypertension resulting in mild limitation of physical activity, they are comfortable at rest and ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. 2
The pathogenesis of PAH involves the increased production of vasoactive compounds, such as endothelin. Endothelin is produced by the endothelial cells and is essential for maintenance of normal vascular tone and function. Tracleer® was the first in a new class of treatments for PAH known as endothelin receptor antagonists. Tracleer® is a dual antagonist as it blocks both ETA and ETB receptors preventing the deleterious effects of endothelin.
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 Tracleer® in Pulmonary Arterial Hypertension (PAH) Tracleer® is an oral dual endothelin receptor antagonist, which is currently licensed for the treatment of PAH; in the United States in PAH Functional Class III and IV to improve exercise capacity and decrease the rate of clinical worsening and in Europe in PAH Functional Class III to improve exercise capacity and symptoms. In the EU Tracleer® is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. Regulatory review for the inclusion of functional class II in the Tracleer® label is ongoing on a worldwide basis.
Tracleer® has been made commercially available by Actelion subsidiaries in the United States, the European Union, Japan, Australia, Canada, Switzerland and other markets worldwide since 2001. In these six years of clinical experience, more than 50,000 patients have been treated with Tracleer®.
About the EARLY study The objectives of the prospective, double-blind, randomized, placebo-controlled, multi-center EARLY3 trial were to investigate whether initiating treatment with Tracleer earlier in the course of the disease would not only affect haemodynamics and exercise capacity, but would also delay clinical worsening in patients with PAH WHO functional class II.
The results from EARLY3 in 185 patients in WHO functional class, reinforce the relentlessly progressive nature of PAH, even in its early stages. This was evident from the deterioration in all evaluated parameters in the placebo group, including the rate of clinical worsening events. The primary endpoints for the EARLY3 trial were changes in pulmonary vascular resistance (PVR) and exercise capacity as measured by a 6-minute walk test (6-MWD). Disease progression was assessed by evaluating two secondary endpoints which included time to clinical worsening and WHO functional class.
PVR improved significantly with a treatment effect of -22.6% in PVR (p <0.0001). 6MWD increased by a mean of 19 meters (p = 0.0758). Significant 77% risk reduction in the time to clinical worsening (p = 0.011) was seen after 24 weeks of bosentan treatment compared with placebo. Time to clinical worsening was defined by symptomatic progression of PAH, hospitalization for PAH or death. The treatment effect was driven by the component symptomatic progression. In addition, bosentan was associated with a lower incidence of worsening functional class (3.4% vs. 13.2%, p = 0.029), providing further evidence of delayed disease progression.
Although the increase in 6-MWD did not reach statistical significance (p = 0.076), this may reflect the fact that, on average, enrolled patients in the EARLY study, who corresponded to those described in the literature as being PAH functional class II, had a relatively well-preserved mean exercise capacity at baseline (435 ± 88 meters), which can be difficult to further improve. A subgroup of patients who were receiving concomitant sildenafil at baseline showed improvements in haemodynamic parameters in the bosentan treatment group consistent with the overall results.
The safety and tolerability profile of bosentan was consistent with that observed in previous placebo-controlled clinical trials.
Other clinical studies with Tracleer in specific patient populations Actelion also conducted clinical trials to further describe the role of bosentan in treating PAH in specific patient populations, such as patients with congenital heart disease (with Eisenmenger syndrome; BREATHE-5) and patients infected with HIV (BREATHE-4). Study results are reflected in the Tracleer® product label. Clinical studies with bosentan in children suffering from PAH (BREATHE-3, FUTURE-1 and -2) have been conducted. A dedicated paediatric formulation with bosentan has been submitted to European Health Authority and is currently under assessment.
About Tracleer® 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 Tracleer® is indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. Tracleer® 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: 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, Tracleer® is only supplied through controlled distribution.
References 1. Tracleer® SmPC 2. Barst RJ, McGoon M, Torbicki A et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43 (Suppl S) :40S-47S. 3. Galiè N, Rubin LJ, Hoeper MM et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. The Lancet 2008; 371: 2093-2100. 4. Sitbon O et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111: 3105-3111. 5. D'Alonzo G et al. Survival in patients with primary pulmonary hypertension. Annals of Internal Medicine 1991; 115:343-349
Actelion Ltd Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer® 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 1700 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SWX Swiss Exchange (ticker symbol: ATLN).
For further information please contact:
Medical Media Contact Kris Matta-Noaman Packer Forbes +44 208 772 1551 kris@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
