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Promising clinical data
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In 2002, Actelion successfully strengthened its global reach by proving its skills in regulatory affairs as well as sales and marketing. The company expanded its development capabilities, capitalizing on the company’s knowledge about the involvement of the endothelin system in various diseases, while simultaneously preparing for clinical programs with new compounds from Actelion’s research efforts.
Actelion continues to manage its products through life-cycle teams with the goal of rapidly moving a drug from inception to initial commercialization and then to global sales. New indications for existing drugs and new drugs in new indications will allow Actelion to grow above and beyond the significant peak-sales potential of Tracleer® in PAH, currently estimated at between USD 400 and 500 million.
A strong development function is key to ensure that a drug’s potential is appropriately profiled in well-defined and executed clinical trials that satisfy the highest standards in the industry. With this in mind, Actelion has built up a development department staffed by professionals with years of experience in the pharmaceutical industry. Their efforts in the BREATHE studies have allowed Tracleer® to reach the market in a record time of less than 26 months after the first of two pivotal studies were initiated.
Actelion’s development efforts have concentrated on enlarging the potential indications for Tracleer® in other endothelin-related diseases (digital ulcerations, pulmonary fibrosis, metastatic melanoma) as well as evaluating the right dosing regimen for the company’s intravenous dual endothelin-receptor antagonist Veletri™, which began evaluation in a Phase III program as a potential agent for the treatment of acute heart failure (AHF) in late 2002.
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PAH as a complication of scleroderma
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Pulmonary arterial hypertension (PAH) is a frequent and often fatal complication of scleroderma, an autoimmune disease afflicting up to 200,000 patients worldwide. In these patients, endothelin acts as a pathogenic mediator, not only leading to PAH, but also at least two other major complications of scleroderma, pulmonary fibrosis and digital ulcerations.
In order to address the potential of Tracleer® in scleroderma, Actelion has chosen a development program to establish the effect of the drug in each complication. With PAH already approved, Actelion has moved its focus to digital ulceration, with a first study concluded in summer 2002. During the same year, Actelion began thorough discussions with key physicians on its clinical trial plans for Tracleer® in pulmonary fibrosis related to scleroderma. First studies will be initiated in early 2003.
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Preventing and treating digital ulcerations
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Systemic sclerosis (scleroderma), an autoimmune rheumatic disease, is characterized by an increased accumulation of connective tissue in skin and internal organs as well as vascular injury and damage. Endothelin, as a pathogenic mediator, is implicated in the vascular damage. Complications in scleroderma, including pulmonary arterial hypertension (PAH) and digital ulcers, are the result of vasculopathy (vascular dysfunction).
Digital ulcerations are a common complication of scleroderma, occurring in 25% or more of patients, with approximately 5,000 severe cases worldwide. A result of the blockage of small blood vessels (obliterative vasculopathy), digital ulcers are very painful and difficult-to-heal open sores that occur on fingers and toes. They often lead to infections, leave depressed scars and adversely impact the ability to perform work and daily activities. In severe cases, gangrene develops, which requires surgery and even amputation.
In 2002, Actelion conducted an international, multi-center, doubleblind, placebo-controlled clinical trial called RAPIDS-1 (RAndomized Placebo-controlled Investigation of Digital ulcers in Scleroderma). The study evaluated whether treatment with Tracleer® could prevent the occurrence of new ischemic digital ulcers in patients with scleroderma.
The results of RAPIDS-1, presented in the late-breaking session of the American College of Rheumatology in New Orleans, showed that patients with existing ulcers taking Tracleer® developed half as many new digital ulcers per patient as those treated with placebo. In this high-risk group, the proportion of patients that did not develop new ulcers during the trial was also greater in the treatment group. In addition, the patients treated with Tracleer® had a significant improvement in hand functionality such as their ability to dress and to wash their hands and hair.
Actelion is currently engaged in discussions with regulatory authorities worldwide to decide on the appropriate design of the next trial in digital ulcerations. The new study, called RAPIDS-2, is expected to commence in the second half of 2003. In the meantime, Actelion has initiated the process of applying for “orphan drug” status in this indication in both the United States and Europe.
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Tracleer® in other fibrotic diseases
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In 2002, Actelion also focused on development opportunities for
Tracleer® in other endothelin-related diseases such as pulmonary fibrosis, a progressive lung disease that is usually fatal. The idiopathic form (no known cause) of pulmonary fibrosis (IPF) afflicts some 100,000 patients worldwide.
In early 2003, as part of its clinical trial program to expand the use of Tracleer®, Actelion initiated two studies, BUILD-1 and 2 ( Bosentan Use in Interstitial Lung Disease ). One study addresses the idiopathic form of the disease and the other study addresses pulmonary fibrosis related to systemic sclerosis (scleroderma). Actelion has chosen an innovative trial design, using a walking test as the primary endpoint of the studies. First results are expected in 2005.
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Endothelin in interstitial lung diseases
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Many acute and chronic lung disorders with variable degrees of pulmonary inflammation and fibrosis are collectively referred to as interstitial lung diseases (ILD). These diseases can be associated with underlying conditions such as systemic sclerosis. More than 75% of these patients develop pulmonary fibrosis, with one million cases worldwide.
In IPF and in ILD caused by scleroderma, inflammation and accumulation of connective tissue (fibrosis) in the lungs destroys structure and function of the respiratory system. Endothelin has major pro-fibrotic and pro-inflammatory effects. Since endothelin concentrations are strongly elevated in ILD, there is solid evidence that endothelin might be involved in these diseases as well. Endothelin receptor antagonism, therefore, may be an effective therapeutic strategy.
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Tracleer® in cancer
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In the first quarter of 2003, Actelion will initiate a first series of studies with Tracleer® in malignant (metastatic) melanoma. Several pre-clinical experiments have shown that in malignant melanoma, endothelin plays a role in the proliferation of abnormal, cancerous cells. In 2002, development plans for Tracleer® in these proliferative diseases were discussed with key experts in the field and experienced personnel were hired to maximize the chances of success of Tracleer®.
The incidence of metastatic melanoma, which may spread locally or metastasize to major organs, is 15 per 100,000 and the disease has a death rate of 2.5 per 100,000. Since current treatments have a response rate of only 15–20% and a cure rate of less than 5%, there is a high unmet medical need for an effective therapy.
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