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ACR Poster Presentation Highlights Clinical Data about Bosentan In Systemic Sclerosis Patients Suffering From Digital Ulceration

Placebo-controlled randomized RAPIDS-2 study shows significant reduction in the occurrence of new digital ulcers

SAN DIEGO, CA -- November 22, 2005 -- Actelion Ltd. announced the poster presentation at the American College of Rheumatology (ACR) of results of RAPIDS-2, a placebo-controlled randomized study that evaluated bosentan (Tracleer^®) in preventing or treating digital ulcerations in patients with systemic sclerosis.

The 188-patient study demonstrated in its first co-primary endpoint a statistically significant reduction in the occurrence of new digital ulcerations (p=0,035, first co-primary endpoint). In terms of the healing of digital ulcerations, the second co-primary endpoint, there was no significant difference between bosentan and placebo.¹

Today, the oral dual endothelin receptor antagonist Tracleer^® is indicated for the treatment of pulmonary arterial hypertension (PAH Functional Class III and IV in the United States, Class III in Europe) to improve exercise ability and decrease the rate of clinical worsening.

As many as 15% of people with systemic sclerosis develop PAH, making it a high risk group for this devastating condition.² Digital ulcers are a common and painful complication of systemic sclerosis with approximately 30-50% of people with systemic sclerosis developing digital ulcers during their lifetime.³

Dr James R. Seibold, MD, Professor of Internal Medicine at the University of Michigan in Ann Arbor, Michigan, USA and Principal Investigator of RAPIDS-2, commented: "It is encouraging to see earlier findings of RAPIDS-1 confirmed. In patients with scleroderma, preventing the occurrence of further digital ulcerations is a valid medical strategy and—as demonstrated in these trials—of benefit to patients."

The RAPIDS-2 findings in detail
The placebo-controlled, randomized study RAPIDS-2 (RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis) enrolled a total of 188 patients in 41 centers worldwide.

Patients with systemic sclerosis and at least one digital ulcer were treated with either bosentan (62.5mg bid for 4 weeks, then 125mg bid for at least 20 weeks and up to 32 weeks) or placebo.

The total number of new ulcers over 24 weeks was 1.9 ± 0.2 for patients on bosentan versus 2.7 ± 0.3 for patients on placebo (P =.035).¹

Using the SHAQ (Scleroderma Health Assessment Questionnaire) scale some improvements in items of hand function (secondary endpoint) were demonstrated in patients treated with bosentan. In particular, hand functions associated with 'dressing' (P =.033) and 'eating' (P =.098) showed improvement with bosentan over placebo at week 24. Pain scores, measured using the SHAQ VAS scale, were improved for bosentan patients at 12 weeks (P =.034).¹

Important information related to prescribing Tracleer^® in the United States of America:

Indication
Tracleer^® is indicated for the treatment of pulmonary arterial hypertension in patients with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening. ⁴

Liver and Pregnancy Warnings
The administration of Tracleer^® requires attention to two significant concerns:

· potential for serious liver injury: Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter; and

· high potential for major birth defects: Pregnancy must be excluded and prevented by two forms of birth control; monthly pregnancy tests should be obtained.

Tracleer^® Prescribing Information.

About the SHAQ scale
The Health Assessment Questionnaire (HAQ) was developed in 1978 by James F. Fries and colleagues at Stanford University and has become one of the most widely used patient-oriented outcome assessment instruments in the world. It has been used predominantly, but not exclusively to measure outcome in patients with rheumatic diseases, including rheumatoid arthritis, osteoarthritis, juvenile rheumatoid arthritis, lupus, scleroderma, ankylosing spondylitis, fibromyalgia, and psoriatic arthritis. The Scleroderma Health Assessment Questionnaire (SHAQ) is a modified version of the HAQ with additional outcome assessments specific for systemic sclerosis.

About Tracleer^® in Pulmonary Arterial Hypertension (PAH)
Tracleer^®, the first oral dual endothelin receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH) and made available by Actelion subsidiaries in the United States, the European Union, Japan, Australia, Canada, Switzerland and other markets worldwide.

In clinical trials leading to the marketing approval of the drug, approximately 11% of PAH patients receiving Tracleer^® experienced abnormal but reversible liver enzyme elevations. It is therefore important that patients undergo monthly liver monitoring. Due to the risk of birth defects, women who are pregnant, or of childbearing age who do not use a reliable method of contraception, must not take Tracleer^®.

REFERENCES:
1. Seibold J et al. Bosentan prevents occurrence but does not speed healing of digital ulcers in patients with systemic sclerosis (SSc). Poster presentation L2: 552. ACR 2005.
2. Black C. Pulmonary arterial hypertension: are we doing enough to identify systemic sclerosis patients at high risk of this rare condition? Rheumatology 2005; 44: 141-142
3. Korn J. et al. Digital ulcers in systemic sclerosis-Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis and Rheumatism 2004; 50:3985-3993


SOURCE: Actelion Ltd

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