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No Effect Shown on Exercise Improvement for Bosentan Clinical Trials

ALLSCHWIL, SWITZERLAND – 28 November 2005 – Actelion Ltd (SWX: ATLN) today announced that in the BUILD program with bosentan (Tracleer®) in patients suffering from either idiopathic pulmonary fibrosis (BUILD-1) or pulmonary fibrosis related to Systemic Sclerosis (BUILD-2), no effect was shown on the primary endpoint of exercise improvement as measured by the 6-minute-walk test.

In the IPF study BUILD-1, although not statistically significant, positive trends were observed for pre-defined secondary endpoints, such as the combined incidence of death or treatment failure at 12 months (36.1% in the placebo group versus 22.5% in the bosentan group; p=0.076; 95% CL 0.37, 1.05), representing a relative risk reduction of 38%.

Treatment failure (per-protocol) was defined as worsening in Pulmonary Function Tests (PFTs) or acute decompensation of IPF. Worsening in PFTs was defined as a decrease from baseline in two of three criteria: decrease from baseline > 10% in FVC; decrease from baseline >15% in DLco; decrease from baseline >4% in O2 saturation (blood gas) at rest or increase from baseline > 8 mmHg in A-a gradient PO2.

These findings provide a strong rationale for pursuing a mortality-morbidity Phase III study. Accordingly, the company will initiate discussions with scientific experts and regulatory authorities worldwide on the design of the Phase III study.

In both studies, the use of bosentan was well tolerated. The observed safety profile was consistent with earlier findings in clinical studies that led to the approval of Tracleer® in pulmonary arterial hypertension (PAH).

Full results of the BUILD program are expected to become available through presentations at upcoming international scientific meetings and publications in peer-reviewed journals.

Comments on BUILD-1
In the IPF study (BUILD-1), pre-defined secondary endpoints related to death or disease worsening - for which the study was not powered - demonstrated trends in favor of bosentan.

Talmadge King Jr. M.D., Professor of Medicine at UCSF, San Francisco General Hospital and Principal investigator of the BUILD-1 study, commented: “I am encouraged that in this well-designed study in patients with IPF, a severe lung disease with no effective therapy, clinically relevant trends were observed in important parameters related to death or disease worsening. This observation should be further investigated in IPF with a clinical program that focuses on improving patients’ long-term outcome.”

Dr. King concluded: “From the results of BUILD-1, we might consider that the 6-minute-walk test - selected for the first time as the primary endpoint in pulmonary fibrosis studies - is not an appropriate endpoint to evaluate the response of this patient population to treatment.”

Jean-Paul Clozel, M.D. and Chief Executive Officer: ”The findings related to the 6-minute-walk test in pulmonary fibrosis are disappointing. Nevertheless, I am very impressed by clinically relevant trends in the pre-defined secondary endpoints related to death or disease worsening. It is now one of Actelion’s key priorities to start discussions with regulatory authorities on the design of a mortality/morbidity study in IPF.”

Comments on BUILD-2
In the study with patients suffering from pulmonary fibrosis related to Systemic Sclerosis (BUILD-2), no effect was observed on either primary or secondary endpoints.

James R. Seibold, M.D., Professor of Internal Medicine at the University of Michigan in Ann Arbor, Michigan, USA and Principal Investigator of BUILD-2, commented: “The fact that we could not demonstrate beneficial effects in BUILD-2 could be related to the slow progression of the disease observed in this study population which was in contrast to the more severe and more rapidly progressing disease observed in BUILD-1. Neverth eless, this well-conducted study has confirmed the long-term safety profile of bosentan in patients with Systemic Sclerosis. In these patients, Tracleer® is an effective treatment for the complication of pulmonary arterial hypertension.”

About the trial design of BUILD-1
The BUILD-1 (Bosentan Use in Interstitial Lung Disease) study was a double-blind, randomized (1:1 bosentan: placebo ratio), placebo-controlled, multicenter study, designed to evaluate the efficacy of bosentan in improving the exercise capacity of patients suffering from idiopathic pulmonary fibrosis (IPF). The study was designed to enroll 132 patients, but enrolled 158 patients.

The primary endpoint of the study was defined as change from baseline in 6-minute walk distance after twelve months.

Secondary and exploratory endpoints focused on changes in pulmonary function tests (PFTs), dyspnea, oxygen saturation during exercise, delay in time to death or treatment failure as well as quality of life.

Patients who completed the 12-month period continued in a double-blind study extension for a total of up to 24 months. Patients meeting pre-set criteria were eligible to enter an open-label active dose extension period.

About the trial design of BUILD-2
The BUILD-2 (Bosentan Use in Interstitial Lung Disease) study was a double-blind, randomized (1:1 bosentan: placebo ratio), placebo-controlled, multicenter study, designed to evaluate the efficacy of bosentan in improving the exercise capacity of patients suffering from fibrosing alveolitis related to Systemic Sclerosis (SSc). The study was designed to enroll 132 patients, but enrolled 163 patients.

The primary endpoint of the study was defined as change from baseline in 6-minute walk distance after twelve months.

Secondary endpoints focused on changes in pulmonary function tests (PFTs), dyspnea, oxygen saturation during exercise as well as quality of life.

Patients who completed the 12-month period were eligible to enter an open-label active dose (long-term) extension study.

Source: Actelion

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