Actelion Ltd.: Successful Prevention Study with Tracleer in Scleroderma-Related Digital Ulcerations -- Presented at the American College of Rheumatology

Actelion to Continue Further Clinical Development with Its Endothelin Receptor Antagonist in Scleroderma-Related Indications


ALLSCHWIL, Switzerland, Oct. 29, 2002 (PRIMEZONE) -- Actelion Ltd. (SWX:ATLN) (Other OTC:ALIOF) announced that Joseph H. Korn, MD, Professor of Medicine and Biochemistry, School of Medicine, Boston University, will present the full results of a successful study with Tracleer(TM) in scleroderma patients suffering from digital ulcerations at today's late-breaking session of the American College of Rheumatology meeting in New Orleans. In this placebo-controlled, multicenter trial, Tracleer(TM) was shown to significantly reduce the occurrence of new digital ulcers (p=0.008).

The lead study investigator in the United States, Joseph H. Korn, MD, said: "The finding that Tracleer(TM) prevents the occurrence of new digital ulcers in scleroderma patients is clinically relevant. A decrease in the number of new digital ulcers means that patients will have less pain and improved function of their hands as well as a lower risk of serious finger infection."

Tracleer(TM), the first orally available dual endothelin receptor antagonist, is already approved and available in major markets worldwide for the treatment of pulmonary arterial hypertension (PAH), a chronic life-threatening condition that severely compromises the function of the lungs and heart. Between 15 to 30 percent of all scleroderma patients develop PAH, the leading cause of mortality in these patients.

Digital ulcerations are also a common complication of scleroderma, occurring in 25 percent or more of patients. Digital ulcerations are a result of the blockage of small blood vessels (obliterative vasculopathy). They are very painful and difficult-to-heal open sores, occurring on fingers and toes, leaving depressed scars and adversely impacting the ability to perform work and daily activities. In severe cases, where gangrene develops, surgery and even amputation may be required.

The Role of Endothelin in Scleroderma

In systemic sclerosis (scleroderma), an autoimmune rheumatic disease, there is increased accumulation of connective tissue in skin and internal organs as well as vascular injury and damage. Complications including pulmonary arterial hypertension (PAH) and digital ulcers are the result of vasculopathy (vascular dysfunction). Endothelin, a pathogenic mediator, is implicated in vascular damage. In addition to causing vasoconstriction, Endothelin also has direct deleterious effects, which cause fibrosis, vascular hypertrophy, and inflammation.

Tracleer(TM), an endothelin receptor antagonist, is effective in treating PAH in scleroderma patients by blocking the detrimental effects of increased endothelin levels. The RAPIDS-1 study was designed to assess the effects of Tracleer(TM) on digital ulcers.

Study Results Prevention of New Digital Ulcers

RAPIDS-1 (RAndomized Placebocontrolled Investigation of Digital ulcers in Scleroderma) is an international, multicenter, double blind, placebo-controlled clinical trial evaluated the prevention of ischemic digital ulcers in 122 patients with systemic sclerosis (scleroderma).

Patients were randomized in a 2:1 allocation to either Tracleer(TM) or placebo for a sixteen-week treatment period. Patients had to have a history of digital ulcerations in the preceding twelve months.

The results of RAPIDS-1 show that patients taking Tracleer(TM) developed half as many new digital ulcers per patient as those treated with placebo (p=0.008). In the subset of high-risk patients, those with digital ulcers at baseline, the mean number of new ulcers was also 50 percent lower in the Tracleer(TM) treated vs. the placebo group (p=0.006). In this high-risk group, the proportion of patients who did not develop new ulcers during the trial was also greater in the treatment group (33% vs. 17%, p=NS).

The impact of treatment on the patient's hand functionality was assessed through a Quality-of-Life questionnaire. Patients treated with Tracleer(TM) had a significant improvement in hand functionality (defined as the ability to dress, to self-groom such as washing hands and hair, as well as the ability to grip objects) compared to placebo (p=0.004).

In terms of safety, the study confirmed the existing safety profile and good tolerability of Tracleer(TM), with 14 percent of patients on Tracleera experiencing elevations of liver aminotransferases more than 3 times the upper limit of normal, with all elevations resolving upon dose reduction or treatment discontinuation.

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

In his presentation, Dr. Korn concluded: "Tracleer(TM) is beneficial in preventing the occurrence of new digital ulcers in patients with scleroderma. This suggests that endothelin may play a pathogenetic role in the development of digital ulcers in scleroderma and that endothelin receptor antagonism may be an effective therapeutic strategy for vascular disease in systemic sclerosis."

Actelion to evaluate further options for continued clinical development

Isaac Kobrin, Head of Clinical Development, said: "While developing Tracleer for the now approved indication PAH, we confirmed that endothelin plays a crucial role in the pathogenesis of scleroderma. Based on the findings of RAPIDS-1, Actelion will further evaluate the benefits of Tracleer(TM) in scleroderma patients, including digital ulcerations."

The company is currently engaged in discussions with the Food and Drug Administration FDA regarding the appropriate design of the next trial in digital ulcerations. Actelion also plans to engage in similar discussions with other regulatory authorities worldwide as well as with clinical experts in the field.

As these discussions continue in the coming months, a new study is expected to start in the second half of 2003. In the meantime, Actelion is in the process of applying for an additional orphan drug indication for Tracleer(TM) in both the United States and Europe beyond PAH, this time for Digital Ulcerations in Systemic Sclerosis.

Actelion is also currently finalizing its clinical development plans for another endothelinrelated complication, pulmonary fibrosis secondary to scleroderma.

Tracleer(TM) today Approved in Pulmonary Arterial Hypertension

Tracleer(TM), the first orally available dual endothelin receptor antagonist, is currently approved and available in the United States, the European Union (Austria, France, Germany, Italy, U.K., others to follow), Canada and Switzerland for the treatment of Pulmonary Arterial Hypertension (PAH), a chronic life-threatening condition that severely compromises the function of the lungs and heart.

Approximately 100,000 people in Europe and the United States are afflicted with either primary pulmonary 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.

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Actelion Ltd.

Actelion Ltd. is a biopharmaceutical company, with its corporate headquarter in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer(TM), an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer(TM) through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union as well as Canada 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 focuses 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).


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