Actelion's Tracleer (bosentan) tablets approved by the US FDA - First oral treatment of pulmonary arterial hypertension

November 21, 2001

ALLSCHWIL, SWITZERLAND - November 20, 2001 -- Actelion Ltd. (SWX New Market: ATLN) today announced that the U.S. Food and Drug Administration (FDA) has approved Tracleer™ (bosentan), an orally active endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension (PAH). Tracleer is indicated to improve exercise ability and decrease the rate of clinical worsening in PAH patients with significant limitation of physical activity (WHO class III and IV).

PAH is a chronic, life-threatening disorder that can severely compromise the function of the lungs and heart. Tracleer 125mg, taken twice a day, is the first approved oral treatment for patients suffering from PAH and is expected to be available to patients in the United States in early December. Regulatory reviews are ongoing in the European Union, Canada, Switzerland and Australia.

"I am extremely proud that our first approved product is such a revolutionary breakthrough in the treatment of pulmonary arterial hypertension, " says chief executive officer, cardiologist and founder of Actelion, Jean-Paul Clozel, MD. "Following substantial investments in drug discovery and development, Actelion has recently also built a strong US affiliate and sales force - with a total of more than 70 employees - in order to provide patient and physician education about Tracleer immediately after launch."

Tracleer represents the first agent to be approved by the FDA from a new class of drugs called endothelin receptor antagonists (ERAs). Levels of endothelin, a potent blood vessel constrictor, are elevated in the plasma and lung tissue of patients with PAH, suggesting a pathogenic role for endothelin in the progression of this condition. Tracleer works by blocking the binding of endothelin to its receptors, thereby preventing the deleterious effects of endothelin upon blood vessels.

Approximately 11 % of 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 may become pregnant, cannot take Tracleer.

Tracleer may be prescribed only through the Tracleer™ Access Program by calling 1-866-228-3546.

"Actelion is committed to bringing this revolutionary treatment to all eligible patients through a comprehensive access program", said Simon Buckingham, President Actelion Pharmaceuticals, U.S. "We are also embarking upon a very extensive education and risk management campaign with the medical community so that patients can derive the maximum benefit from the use of Tracleer".

Clinical Background The FDA approval is based on two successfully concluded pivotal trials, the larger of which is known as the BREATHE-1 (Bosentan: Randomized Trial of Endothelin Receptor Antagonist THErapy) trial. BREATHE-1 principle investigator Lewis Rubin, MD, Professor of Medicine and Director, Pulmonary and Critical Care Medicine, University of California at San Diego commented: "Tracleer is a milestone in the treatment of pulmonary arterial hypertension. Now, for the first time, patients and their families have access to an oral treatment. In the past, the only approved treatment required an indwelling central IV line and patients had to carry a continuous infusion pump at all times."

In the 213-patient BREATHE-1 trial, twice-daily Tracleer (125 mg b.i.d. and 250 mg b.i.d.) demonstrated - in both primary and secondary PAH - statistically significant improvements versus placebo in the primary efficacy endpoint of the study, exercise capacity. The overall treatment effect for both doses of Tracleer combined was a 44-meter improvement in walking distance as measured by a six-minute walk test, compared to placebo (p=0.0002). This improvement was maintained for up to seven months. Treatment with Tracleer also was associated with a significant delay in the time to clinical worsening as defined as death, hospitalization, worsening PAH or initiation of intravenous therapy (p=0.0015), as well as significant improvement in functional status and breathlessness.

A smaller 32-person study recently published in the medical journal The Lancet, demonstrated that patients receiving Tracleer had significant improvements in exercise capacity and hemodynamics (blood circulation). .
About PAH

Approximately 100,000 people in the U.S. and Europe are afflicted with either primary pulmonary arterial hypertension or secondary forms of the disease related to conditions or tissue disorders that affect the lungs, such as scleroderma, lupus, HIV/AIDS, congenital heart disease or the use of certain appetite suppressants.

The first signs of the disease, such as mild shortness of breath, fatigue and difficulty exercising, are so subtle that the disease is often either misdiagnosed or not diagnosed until the patient's condition is far advanced. The survival rate for PAH in untreated patients is only 40 to 55 percent at two years from the onset of symptoms. Once patients reach more advanced stages of PAH (WHO Class III and IV), they often have no choice but to go on prostacyclin therapy, which requires a 24-hour infusion pump and an intravenous line implanted through the chest directly into the patient's heart. Ultimately, many patients require lung transplantation.

Regulatory Background

Actelion submitted a New Drug Application (NDA) for Tracleer in pulmonary arterial hypertension to the U.S. Food and Drug Administration in November 2000 and to the European Authorities in February 2001. Tracleer also is currently under review in Switzerland, Canada and Australia. Authorities in the U.S., the European Union and in Australia have granted Tracleer Orphan Drug status in pulmonary arterial hypertension. The company is currently studying Tracleer for children under the age of 12 suffering from PAH, as well as the concomitant use of Tracleer in patients who receive intravenous prostacyclin therapy.

Tracleer is currently also in Phase III trials to investigate its potential as a possible treatment of chronic heart failure (CHF). Upon successful completion of this program, Genentech Inc. has the option to become a co-promotion partner for Tracleer in both indications (CHF and PAH) in the United States.

For the background documentation on Tracleer™ and pulmonary hypertension, please check our website under

Actelion Ltd

Actelion Ltd is a biopharmaceutical company headquartered in Allschwil/Basel Switzerland and has a substantial US operation based in South San Francisco. Actelion 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 focuses on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the Swiss Stock Exchange (SWX New Market ATLN).

Contact at Actelion Ltd, Gewerbestrasse 16, CH-4123 Allschwil:

Media/Investor Contacts Roland Haefeli +41 61 487 34 58 MCS Public Relations Kristen Supchak 1-800-477-9626 ext. 32


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