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Clinical Development - Tracleer® |
THE ACTELION ANNUAL REPORT 2003 |
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| Clinical Development - Tracleer® |
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| Long-term data of Tracleer® in PAH |
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In May 2003, Actelion announced the analysis of long-term follow-up data of primary pulmonary hypertension (PPH) patients from Tracleer® pivotal registration studies. Analysis of the data showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment with Tracleer®
(V. McLaughlin et al., “The effect of first-line bosentan on survival of patients with primary pulmonary hypertension,” Poster, WHO, 2003).
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| Tracleer® supportive trials |
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Tracleer® has been approved for use in pulmonary arterial hypertension (PAH), both in primary forms of the disease as well as PAH related to other diseases. In order to generate additional experience and data in specific patient populations, Actelion has initiated several post-approval Phase IV studies.
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In September 2003, results of a study assessing Tracleer® in the treatment of PAH related to HIV (human immunodeficiency virus) infection was announced at the annual European Society of Cardiology meeting (ESC). Analysis of the open-label study BREATHE-4 (Bosentan Randomized trial of Endothelin Antagonist THErapy for Pulmonary Hypertension-4) showed a statistically significant improvement in hemodynamic parameters, exercise capacity (6-minute walk test), functional status and quality of life compared to baseline after 16 weeks of treatment with Tracleer® (O. Sitbon et al., “Bosentan improves hemodynamic and clinical function in pulmonary arterial hypertension associated with HIV infection: The BREATHE-4 study,” Poster, WHO, 2003) The results also indicate that Tracleer® can be given together with antiretroviral therapy and is well tolerated.
The objective of the EARLY (Endothelin Antagonist tRial in miLdly sYmptomatic PAH patients) trial is to substantiate the potential of Tracleer® in the treatment of patients with Class II disease who are mildly symptomatic. The goal is to improve the patient‘s exercise capacity and also to slow down disease progression. Results of this Phase III, double-blind, placebo-controlled trial, which will be initiated in the second quarter of 2004, are expected in early 2006.
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"We aim to develop new products with a focus on innovative treatments for high unmet medical needs and to maximize the value of our existing products by seeking additional indications for these drugs" |
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| Targeting complications of scleroderma |
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Scleroderma is an autoimmune disease characterized by an increase in connective tissue in skin and internal organs that accompanies vascular inflammation and vessel obliteration. Endothelin is implicated in this process. Digital ulcers (DUs) are a common complication of scleroderma, affecting some 25% of patients (approximately 5,000 severe cases worldwide). These ulcers are very painful, often associated with infection, and are very difficult to heal. Gangrene leading to amputation of the fingers occurs in severe cases.
In 2002, RAPIDS-1 (RAndomised Placebo-controlled Investigation of Digital ulcers in Scleroderma), Actelion’s first study with Tracleer® in patients with digital ulcers, showed promising results: Bosentan prevented the occurrence of new DUs in patients with scleroderma. The treatment resulted in significant improvement in hand functionality (e.g. grip, hygiene, dressing, grooming). Bosentan was safe and well tolerated. In April 2003, the design for the new Phase III study RAPIDS-2 was discussed with the FDA and EMEA. In winter, the patient recruitment started. RAPIDS-2 examines the effects of Tracleer® on the prevention and healing of digital ulcers in patients with active digital ulcers. The results are expected in late 2005.
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| Treating fibrotic diseases |
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Endothelin is overexpressed in two forms of interstitial lung disease: idiopathic pulmonary fibrosis and pulmonary fibrosis due to scleroderma. Endothelin blockade with Tracleer® may provide a new treatment opportunity. Currently, pulmonary fibrosis is treated with drugs that have never been shown to be effective in clinical trials, such as corticosteroids or gamma-interferon, which have no proven effect on disease progression or survival rates. Phase II/III trials with Tracleer® in the indications of idiopathic pulmonary fibrosis for BUILD-1 (Bosentan Use in Interstitial Lung Disease) and pulmonary fibrosis secondary to scleroderma (BUILD-2) were initiated in 2003. Results are expected in late 2005 and early 2006.
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| Testing in skin cancer |
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Several pre-clinical experiments have shown that endothelin plays a role in the proliferation and growth of cancerous cells, particulary melanocytes. These findings provide the rationale to assess the effects of Tracleer® in malignant melanoma. This condition occurs in 15 of every 100,000 people, and is increasing each year. Median life expectancy in metastatic melanoma, where the tumor has spread locally and to major organs, is less than six months. Current therapies induce a response in 15–20% of patients and less than 5% are cured.
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In 2003, Actelion initiated a proof-of-concept study with Tracleer® in patients with late-stage metastatic melanoma evaluating tumor response and survival. The patient enrollment has been completed and results of this Phase II trial are expected in 2004.
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