FDA today announced the approval of Tracleer (bosentan) tablets to improve the exercise ability of patients with a rare but fatal lung disorder called pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is defined as abnormally high blood pressure in the arteries between the heart and lungs. PAH significantly reduces the ability of patients to exert themselves physically without becoming short of breath. PAH significantly shortens the life span of patients because it leads to heart failure.

Tracleer blocks the action of endothelin, a substance made by the body. Endothelin narrows blood vessels and elevates blood pressure. Although endothelin is present in healthy people, high concentrations of the hormone have been found in the plasma and lungs of patients with PAH suggesting it is capable of causing the disease.

The use of Tracleer requires attention to two significant risks: liver toxicity and the drug's potential to damage a fetus. In order to ensure careful attention to monitoring for these risks, Tracleer will be available only through a direct distribution program from the drug's manufacturer, Actelion Pharmaceuticals US, Inc., of South San Francisco, Calif. It will not be available in commercial pharmacies.

These safety issues are highlighted in a black box warning in the drug's labeling for health professionals and explained in a brochure for patients. This information is known as a Medication Guide and must be distributed each time Tracleer is dispensed.

Specifically, the black box information warns that liver enzyme levels must be measured before initiation of treatment with Tracleer and monthly thereafter to avoid liver injury. To date, the elevation of liver enzymes caused by Tracleer has been resolved without causing permanent liver damage.

Because of its potential to cause birth defects, Tracleer must not be prescribed to pregnant women. Female patients of childbearing potential must therefore take measures to prevent pregnancy, and monthly pregnancy testing will be required. Oral, injected and implanted contraceptives may not be reliably effective, because Tracleer may alter their metabolism in a way that reduces the effectiveness of hormonal contraceptives, so these methods must be supplemented by other methods or barrier methods must be used. Therefore, it is important for patients to consult with a gynecologist or other physician knowledgeable about contraceptives.

The FDA with the help of the Cardiovascular and Renal Drugs Advisory Committee determined that Tracleer is an effective treatment based on the results of two randomized, placebo-controlled clinical trials involving a total of 245 patients. In both studies, Tracleer or placebo was given in addition to any other medications currently prescribed. In both studies, treatment with Tracleer resulted in a significant increase compared to placebo in the 6-minute walking distance of patients receiving Tracleer, an additional 35 meters in one study and 54 meters in another. The improvement in walking distance was apparent after one month and fully developed by about two months of treatment. Significant improvement was maintained for up to seven months of Tracleer treatment.




Further regulatory progress for Tracleer in Pulmonary Arterial Hypertension

Allschwil, Switzerland - June 20, 2001 - Actelion Ltd announced today that the company has been informed that its application for Tracleer in Pulmonary Arterial Hypertension (PAH) will be reviewed by the U.S. Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee on 9 August 2001 (Thursday). Actelion filed for marketing authorization for Tracleer in the United States in the fall of 2000.

More recently, Actelion has filed in Switzerland and the Swiss regulatory authority (IKS) has granted fast track review. Regulatory review is ongoing in the European Union, Australia and Canada. Tracleer is the first endothelin receptor antagonist ever to have been submitted for regulatory review.

Actelion Ltd, a biopharmaceutical company headquartered in Allschwil, Switzerland, is a leading player in creative science related to the endothelium - the single layer of cells separating every blood vessel from the blood stream. Actelion concentrates on developing and bringing innovative drugs to patients. Tracleer and Veletri, its two flagship drugs, are in late stage development for several cardiovascular disorders, including chronic and acute heart failure as well as pulmonary arterial hypertension. In addition, Actelion is conducting drug discovery programs in cardiovascular diseases, malaria, Alzheimer's disease and cancer.

 

Oral Endothelin Receptor Antagonist Tracleer Meets Primary Endpoint in Pulmonary Arterial Hypertension Study

-- Actelion and Genentech announce positive results of Tracleer Phase III trial; Data will supplement US and European market authorization filing --

ALLSCHWIL, SWITZERLAND and SOUTH SAN FRANCISCO, -- 2 May 2001 -- Actelion Ltd and Genentech, Inc. announced positive results today from a Phase III trial (BREATHE-1) of the first orally active endothelin receptor antagonist, Tracleer (bosentan) in pulmonary arterial hypertension (PAH). PAH is a chronic life-threatening condition that severely compromises the function of the lungs and heart. In the BREATHE-1 trial, Tracleer demonstrated statistically significant improvements in the primary efficacy endpoint of the study, exercise capacity.

"For the first time in a large scale clinical trial, an oral agent has demonstrated the potential to dramatically improve patient outcome in PAH," said BREATHE-1 lead investigator Lewis Rubin, MD, Professor of Medicine/Director, Pulmonary and Critical Care Medicine, University of California at San Diego.

"These findings demonstrate Tracleer may be an important new treatment for PAH patients that is convenient to administer orally."

BREATHE-1 (Bosentan: Randomized Trial of Endothelin Receptor Antagonist THErapy for Pulmonary Hypertension), a double-blind, placebo-controlled, multicenter trial, was designed to evaluate the safety and efficacy of two dose levels of Tracleer (125 mg b.i.d. and 250 mg b.i.d.). The primary endpoint of the study was the change from baseline in exercise capacity, as measured by a six-minute walk test at 16 weeks. The 213-patient trial randomized patients into three arms, the first receiving a starting dose of 62.5 mg bid of

Tracleer doubled to 125 mg bid after four weeks of treatment, the second receiving a starting dose of 62.5 mg bid increased to 250 mg bid after four weeks, and the third arm receiving placebo.

Patients receiving Tracleer were able to walk statistically significantly longer distances in the six-minute walk test after 16 weeks, compared to placebo. The overall treatment effect for both doses of Tracleer combined was a 44 meter improvement in walking distance, compared to placebo (p=0.0002). This effect was statistically significant for both Tracleer treatment groups. Significant positive effects were also observed in clinically important secondary endpoints.

"These initial results confirm the findings from the earlier Phase III trial of Tracleer and highlight its potential for the treatment of pulmonary arterial hypertension," said Hal V. Barron, MD, Genentech's senior director of Cardiopulmonary Research.

Tracleer was well tolerated and the overall incidence of adverse events was similar across the three treatment groups. The incidence of elevated liver enzymes (reported as an adverse event) was 3% for placebo, 5% for 125 mg Tracleer b.i.d., and 14% for 250 mg Tracleer b.i.d. None of these elevations in the Tracleer groups were judged serious by the investigators. There was a higher incidence of worsening of PAH in the placebo group (19%) versus the Tracleer treatment group (7%). The overall rate of serious adverse events was similar between Tracleer and placebo treated patients.

"The positive findings of the Tracleer BREATHE-1 study reinforce our belief that the class of endothelin receptor antagonists may have an important clinical role to play in pulmonary arterial hypertension," said Jean-Paul Clozel, Actelion Ltd Chief Executive Officer and company-co-founder. "We will continue to work closely and expeditiously with regulatory authorities to bring Tracleer to patients suffering from pulmonary arterial hypertension."

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 the European Authorities in February 2001. Filing was based upon an earlier study of similar design. The BREATHE-1 data will supplement these submissions, as well as submissions pending in Canada and Australia. U.S., European and Australian regulatory authorities have granted Tracleer Orphan Drug status in pulmonary arterial hypertension.

Actelion and Genentech signed an agreement in December 2000 for the co-promotion of Tracleer for pulmonary arterial hypertension and chronic heart failure in the USA, with Actelion taking the lead in the development and commercialization. Tracleer is currently in Phase III trials for the treatment of chronic heart failure.

Pulmonary arterial hypertension (PAH) is a chronic life-threatening condition that can involve the lungs, heart and other organs. Pulmonary hypertension carries a survival rate in untreated patients of only 40 to 55 percent at two years from the onset of symptoms.

Studies estimate that 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. One available treatment option for pulmonary arterial hypertension involves use of IV medication that must be administered 24 hours a day and seven days a week via a central intravenous catheter.

 

Actelion Ltd, a biopharmaceutical company headquartered in Allschwil, Switzerland, is the global leader in creative science related to the endothelium - the single layer of cells separating every blood vessel from the blood stream. Actelion concentrates on developing and bringing innovative drugs to patients. Tracleer and Veletri (tezosentan), its two flagship drugs, are in late stage development for several cardiovascular disorders, including chronic and acute heart failure as well as pulmonary arterial hypertension. In addition, Actelion is conducting drug discovery programs in cardiovascular diseases, malaria, Alzheimer's disease and cancer. Actelion is quoted on the Swiss Stock Exchange (SWX New Market: ATLN).

Genentech, Inc., is a leading biotechnology company that discovers, develops, manufactures and markets human pharmaceuticals for significant unmet medical needs. Fourteen of the currently approved biotechnology products stem from Genentech science. Genentech markets nine biotechnology products directly in the United States. The company has headquarters in South San Francisco, California, and is traded on the New York Stock Exchange under the symbol DNA.

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