Pivotal Pulmonary Arterial Hypertension Study Concludes That Early Detection and Intervention is Key to Delay Disease

LAVAL, QUEBEC, Sep 23 (MARKET WIRE) --
Actelion Pharmaceuticals Canada announced today that data presented at
the recent European Cardiology Society meeting, and also published in The
Lancet(1) show that, even in mildly symptomatic pulmonary arterial
hypertension (PAH) patients (WHO functional class II - WHO FC II), the
disease progresses very rapidly, such that patients can worsen to the
most severe, WHO functional class III and IV in a short period of time.
The randomized, placebo-controlled EARLY (Endothelin Antagonist tRial in
miLdlY symptomatic PAH patients) trial is the first and only clinical
trial conducted exclusively in a specifically dedicated WHO FC II PAH
patient population.

Dr. Sanjay Mehta, Associate Professor of Medicine at the University of
Western Ontario and Director, Southwest Ontario Pulmonary Hypertension
Clinic, London Health Sciences Centre, commented: "The results from EARLY
highlight/emphasize the relentlessly progressive nature of PAH, even in
its early stages. It is of paramount importance to screen high risk
patients to diagnose PAH in a timely fashion. It is also crucial that all
PAH patients, regardless of functional class, be closely monitored for
the earliest signs and symptoms of PAH progression and that treatment of
all symptomatic PAH patients be considered to prevent PAH progression and
worsening."

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.

The findings of EARLY indicate that treatment with bosentan may be
beneficial for WHO FC II PAH patients. In EARLY, bosentan (Tracleer(R))
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.

A highly significant reduction in PVR of 22.6% (p less than 0.0001) and a
significant 77% risk reduction in delaying the time to clinical worsening
(p equals 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 equals
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 equals
0.076). This may reflect the fact that, on average, patients in EARLY had
a relatively well-preserved exercise capacity, which therefore can be
difficult to further improve.

The safety and tolerability profile of bosentan was consistent with that
observed in previous placebo-controlled clinical trials(2),(3).

Dr. Mehta commented: "The EARLY trial clearly demonstrates that without
treatment, even mildly symptomatic patients experience PAH progression
within a short period of time. In order to properly delay the progression
of PAH and increase patients' chances of survival, it is imperative to
diagnose patients in the early stages of their disease cycle, ideally WHO
functional class II, and treat them with an evidence-based approach as
soon as possible."

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(2) 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.

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(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 of PAH on a patient's life in terms of symptoms and ability to
tolerate physical activity. Class II patients are defined as patients
with pulmonary hypertension resulting in mild limitation of physical
activity, such that they are comfortable at rest but ordinary physical
activity causes undue dyspnea or fatigue, chest pain or near syncope(6).

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(R) was the first in a new class of treatments for PAH
known as endothelin receptor antagonists. Tracleer(R) is a dual
antagonist as it blocks both ETA and ETB receptors preventing the
deleterious effects of endothelin.

It is estimated that PAH affects somewhere in between 2,000 and 10,000
Canadians, with approximately 500 new cases diagnosed each year. PAH
knows no boundaries affecting children, women and men of all ethnicities
and ages. Symptoms of PAH include persistent, unexplained shortness of
breath, chest pain, fatigue, intolerance to exercise, dizziness, fainting
and swollen feet and /or ankles.

About Tracleer(R) in Pulmonary Arterial Hypertension (PAH)

Tracleer(R) is an oral dual endothelin receptor antagonist, which is
currently approved in Canada for the treatment of PAH in patients with
WHO functional class III or IV primary pulmonary hypertension, or
pulmonary hypertension secondary to scleroderma or congenital heart
disease or human immunodeficiency virus in patients who did not respond
adequately to conventional therapy.

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), patients infected with HIV (BREATHE-4). Study results are
reflected in the Tracleer(R) product monograph. A clinical study with
bosentan in children suffering from PAH (BREATHE-3) has resulted in the
ongoing clinical evaluation of a specific children formulation of
bosentan.

Tracleer(R) 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(R).

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 are recommended.

References

1. Galie 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.

2. 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).

3. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary
arterial hypertension. NEJM 2002; 346: 896-903 (BREATHE-1).

4. 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

5. 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.

6. 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(R), an orally available dual endothelin receptor antagonist, has
been approved as a therapy for pulmonary arterial hypertension. Actelion
markets Tracleer(R) 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).

Contacts:
Chrome Communications
(905) 567-1406

Chrome Communications
Alon Barmapov
(905) 567-1406 ext. 223 or (647) 405-1352
Email: alon@chromecommunciations.ca

Chrome Communications
Ashley Jennison
(905) 567-1406 ext. 222
Email: ashley@chromecommunications.ca

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