Tracleer® (bosentan) receives EU approval for treatment of patients with mildly symptomatic Pulmonary Arterial Hypertension

ALLSCHWIL/BASEL, SWITZERLAND - 04 August 2008 - Actelion Ltd (SWX: ATLN) announced today that Tracleer® (bosentan), a dual endothelin receptor antagonist, has been approved in the European Union for the treatment of patients with mildly symptomatic pulmonary arterial hypertension (PAH WHO functional class FC II). Since 2002, Tracleer® has been approved and available in the European Union for PAH patients with WHO FC III.

Tracleer® is the first PAH treatment ever to be investigated in a clinical study that exclusively enrolled patients with mildly symptomatic WHO FC II. This 185-patient randomized, double-blind, placebo-controlled study provided the basis for this EU approval. The indication extension reads: “Some improvements have also been shown in patients with PAH WHO functional class II (see section 5.1)” 1

Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion, commented: “The EARLY study has demonstrated that even patients with mild symptoms are at risk of rapid deterioration. I am very proud that Actelion - together with the scientific community - has been able to demonstrate the important role of Tracleer® in delaying disease progression in these patients. Our dual endothelin receptor antagonist Tracleer® is the only PAH medicine to have demonstrated a delay in disease progression in three independent placebo-controlled, randomized clinical studies. Actelion will now communicate these important clinical findings to encourage early diagnosis and intervention.”

The results from EARLY (Endothelin Antagonist tRial in miLdlY symptomatic PAH patients) published in “The Lancet” in June2, document the relentlessly progressive nature of PAH, even in its early stages, and highlight the need for earlier treatment and intervention in PAH management. The PAH progression 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 EARLY trial were changes in pulmonary vascular resistance (PVR) and exercise capacity as measured by a 6-minute walk test (6MWD). PAH progression was assessed by evaluating two secondary endpoints which were time to clinical worsening and change in WHO functional class.

The key results of the EARLY study were:

* PVR improved significantly, with a reduction of 22.6 percent (p <0.0001) after six months of bosentan compared with placebo.
* 6MWD increased by a mean of 19 meters (p = 0.0758). Statistical significance was not seen in the 6MWD. However, this may reflect the fact that, on average, enrolled patients had a relatively well-preserved mean exercise capacity at baseline, which can be difficult to further improve.
* A significant 77 percent risk reduction in time to clinical worsening (p = 0.011) was seen after six months of bosentan treatment compared with placebo. Time to clinical worsening was defined by symptomatic progression of PAH, hospitalization for PAH or death. Patients receiving bosentan had a lower incidence of worsening functional class (3.4 percent compared to 13.2 percent when receiving placebo,
p = 0.0285), providing further evidence of delayed PAH progression.
* A subgroup of patients who received concomitant sildenafil showed improvements in PVR and 6MWD consistent with the overall results.
* The safety and tolerability profile of bosentan in the EARLY study was consistent with that observed in previous placebo-controlled clinical trials.3,4


There are four WHO functional classes (FC) 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. WHO 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 syncope.5 Despite being mildly symptomatic, these patients still suffer from a severe and rapidly progressive disease.

Regulatory proceedings to extend the label for bosentan to include PAH patients in WHO FC II are ongoing in the US and other territories worldwide.

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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.6 If untreated, PAH carries a very poor prognosis with a median survival of 2.8 years after diagnosis.7

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.5

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 as well as PAH Functional Class II where some improvements have also been shown. 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 seven years of clinical experience, more than 50,000 patients have been treated with Tracleer®.

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 a controlled distribution.

References

1. Tracleer® SPC
2. 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. Lancet 2008;371: 2093-2100.
3. 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. Lancet 2001;358:1119-23 (Study 351).
4. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. NEJM 2002;346:896-903 (BREATHE-1).
5. 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.
6. 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.
7. 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.

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).

Last update: 04 Aug 2008