Pivotal Pulmonary Arterial Hypertension Study Published in the Lancet Concludes That Bosentan (tracleer) Demonstrates Benefits in Patients with Mildly Symptomatic WHO Functional Class II Disease
ALLSCHWIL, SWITZERLAND - 20 June 2008 - Actelion Ltd (SWX: ATLN) announced today that data published in The Lancet show that, in mildly symptomatic pulmonary arterial hypertension (PAH) patients (WHO functional class II - WHO FC II), bosentan (Tracleer®) prevented clinical deterioration by significantly delaying time to clinical worsening and reduced the number of patients worsening to WHO FC III/IV. A significant reduction in pulmonary vascular resistance and a positive trend in increasing the 6MWD were also observed. The randomized, placebo-controlled EARLY (Endothelin Antagonist tRial in miLdlY symptomatic PAH patients) trial is the first and only trial conducted exclusively in a dedicated FC II PAH patient population.
Professor Nazzareno Galié of the University of Bologna, Italy and lead investigator commented: "The EARLY trial demonstrates that without treatment, even mildly symptomatic patients experience PAH progression within a short period of time. In contrast, treatment with bosentan significantly delayed PAH progression while improving hemodynamic parameters."
The findings of EARLY indicate that treatment with bosentan may be beneficial for WHO FC II PAH patients. Actelion is working with authorities in the US and Europe and in other countries worldwide to expand the label for Tracleer® to include WHO FC II.
EARLY is the third randomized controlled trial with bosentan, to provide data that show a consistent significant effect on delaying PAH progression and reducing disease severity. The data from the other two pivotal trials, Study 351 and BREATHE-1[3 trial, which both investigated bosentan in FC III and IV patients, were published in The Lancet and the New England Journal of Medicine respectively.
The objectives of the EARLY trial were to investigate the effects of bosentan specifically in PAH patients in WHO FC II and to gain more insight into early stage disease. The co-primary endpoints were changes in pulmonary vascular resistance (PVR) and exercise capacity (6MWD). Disease progression was assessed by the secondary endpoints time to clinical worsening and WHO functional class.
A highly significant reduction in PVR of 22.6% (p <0.0001) and a significant 77% risk reduction in delaying the time to clinical worsening (p = 0.011) were seen after six months of bosentan treatment compared with placebo. Time to clinical worsening, defined by death, hospitalization for PAH and symptomatic progression of PAH, showed that more patients remained stable without signs of deterioration in the bosentan-treated group compared with placebo (3.4% vs. 13.2%, p = 0.029). In addition, a significant delay in WHO functional class deterioration was observed in the bosentan group compared with placebo, providing further evidence of delayed disease progression. The improvement in 6MWD did not reach statistical significance (p = 0.076). This may reflect the fact that, on average, patients in EARLY had a relatively well-preserved exercise capacity, which therefore can be more difficult to improve.
The safety and tolerability profile of bosentan was consistent with that observed in previous placebo-controlled clinical trials., 
Professor Gérald Simonneau, Hôpital Antoine Béclère, Université Paris-Sud, France commented: "The results from EARLY show the relentlessly progressive nature of PAH, even in its early stages. It is of paramount importance to screen high risk patients to attain a timely diagnosis and then to treat these patients with an evidence-based approach. It is also crucial that all PAH patients, regardless of functional class, are routinely monitored for the earliest signs and symptoms of PAH progression."
A subgroup of patients who received concomitant sildenafil showed improvements in PVR and 6MWD consistent with the overall results.
Further evidence of the effect of bosentan on hemodynamics is provided by the reduction of NT-proBNP plasma concentration in the bosentan-treated group compared to the increase in the placebo-treated patients. It is generally considered that a decrease in plasma concentration of NT-proBNP following targeted PAH therapy is a predictive factor for patient outcome.
An open-label extension of EARLY is ongoing to establish the impact of early intervention on long-term patient outcome.
Notes to 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. If untreated, PAH carries a very poor prognosis with a median survival of 2.8 years after diagnosis.
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.
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.
Actelion also conducted clinical trials to further describe the role of bosentan in treating PAH in specific patient populations, such as patients with Eisenmenger syndrome, a congenital heart disorder (BREATHE-5), patients infected with HIV (BREATHE-4). Study results are reflected in the Tracleer® product label. A clinical study with bosentan in children suffering from PAH (BREATHE-3) has resulted in the ongoing clinical evaluation of a specific childrens formulation of bosentan.
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 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 a controlled distribution.
References  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.  Channick RN, Simonneau G, Sitbon O et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. The Lancet 2001; 358: 1119-23 (Study 351).  Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. NEJM 2002; 346: 896-903 (BREATHE-1).  Sitbon O, Humbert M, Jais X et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111: 3105-3111  D'Alonzo GE, Barst RJ, Ayres SM et al. Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med 1991; 115: 343-349.  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
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).
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Posted: June 2008