Actelion Pharmaceuticals Ltd (CH) - BUILD-3 study with bosentan in idiopathic pulmonary fibrosis does not meet primary endpoint
ALLSCHWIL/BASEL, SWITZERLAND - 01 March 2010 -
Actelion Ltd (SIX: ATLN) today announced the initial results of BUILD-3, a clinical study evaluating the safety and efficacy of bosentan in patients suffering from idiopathic pulmonary fibrosis. While there was a consistent trend in favor of bosentan, the primary endpoint, reduction in morbidity/mortality, was not met (p=0.21). The well characterized safety profile of bosentan was confirmed.
Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "We are naturally disappointed with this outcome. While in BUILD-3 there is a consistent trend in favor of bosentan, these findings do not support initiating regulatory proceedings."
Jean-Paul Clozel continued: "We remain convinced that endothelin receptors are important targets for potential future treatments in this poorly understood and rapidly progressing form of pulmonary fibrosis. The results of BUILD-3 suggest that a more complete blockade of both endothelin receptors - as potentially achieved with macitentan - might be needed."
The 150 patient exploratory study with Actelion's highly potent, tissue-targeting endothelin receptor antagonist, macitentan, is currently enrolling patients with idiopathic pulmonary fibrosis. The study is expected to be fully enrolled later this year and report data in second half of 2011.
Continued commitment to innovation
Bosentan, an orally available dual endothelin receptor antagonist, is already approved worldwide for the treatment of pulmonary arterial hypertension under the brand name Tracleer®. In the European Union and in other territories, Tracleer® is also approved for the reduction of new digital ulcers in patients with systemic scleroderma. Since market introduction in late 2001, more than 80'000 patients worldwide have been exposed to Tracleer®
Jean-Paul Clozel added: "Our commitment to PAH specifically and innovation in general remains strong. In PAH, we will continue to appropriately promote Tracleer®, Ventavis® and soon - starting in the United States - a new formulation of intravenous epoprostenol with improved thermal stability and expand the PAH market further. Actelion is also continuing its efforts to advance Zavesca® as an important treatment option in type 1 Gaucher disease and the only treatment option for Niemann-Pick Type C, currently approved in the European Union and under regulatory review in the US."
Jean-Paul Clozel concluded: "We are committed to innovation, with a total of 11 compounds in various stages of clinical development. In the second half of 2010, we expect results from the late-stage study CONSCIOUS-2, evaluating the safety and efficacy of clazosentan in non-traumatic subarachnoid hemorrhage in patients post aneurysmal clipping."
BUILD-3 (Bosentan Use in Interstitial Lung Disease) is a multicenter, double-blind, randomized, placebo-controlled, parallel group, event-driven morbidity/mortality study evaluating the safety and efficacy of bosentan 125mg bid in IPF patients. BUILD-3 enrollment was completed in November 2008 with 616 patients. The study was randomized with 2 bosentan-treated patients to 1 placebo patient. A total of 252 events were recorded in the study. The primary endpoint was not met (p=0.21), but there were consistent trends in favor of bosentan.
Following completion of full data analysis, BUILD-3 findings will be presented in upcoming scientific congresses and peer-reviewed publications.
No further studies with bosentan in IPF will be undertaken.
About BUILD-1 In November of 2005, Actelion reported the results of BUILD-1, a clinical study in idiopathic pulmonary fibrosis. Although not statistically significant for the primary end-point 6-Minute-Walk-Test, positive trends for predefined secondary end-points were observed, such as the combined incidence of disease progression or death at 12 months (36.1% in the placebo group versus 22.5% in the bosentan group), representing a relative risk reduction of 38% (95% CI, -5 to 63%; p=0.078). 
About Idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis is a progressive and usually fatal disease of the lung interstitium. It is estimated that there are at least 60,000 patients worldwide with a confirmed diagnosis of idiopathic pulmonary fibrosis (IPF).
In IPF, patients experience progressive dyspnea due to loss of lung function and scarring of the lung. As tissue becomes thicker it causes an irreversible loss of the tissue's ability to transfer oxygen into the bloodstream. Endothelin-1, besides its potent vasoconstriction properties, has direct pro-fibrotic and pro-inflammatory effects. Since endothelin concentrations are elevated in interstitial lung disease, there is also evidence implicating endothelin in this disease.
For patients with IPF outside Japan, there are currently no approved therapies available.
Notes to the Editor
About pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disorder characterized by abnormally high blood pressure in the arteries between the heart and lungs of an affected individual. The function of the heart and lungs is severely compromised, manifested by a limited exercise capacity, and, ultimately, a reduced life expectancy. Approximately 100,000 people in Europe and the United States are afflicted with either primary or secondary forms of the disease related to conditions or tissue disorders that affect the lungs, such as scleroderma, lupus, HIV/AIDS or congenital heart disease.
PAH is associated with structural changes in both the pulmonary vasculature and the right ventricle. Recent advances  in the understanding of the pathogenic factors leading to the pulmonary vascular disease have led to the development of new therapies targeting specific pathways (the prostacyclin pathway; the endothelin pathway; and the nitric oxide pathway) . The available therapies have positive effects in PAH, but they do not provide a cure, and in many patients the disease will progress. PAH remains a serious life-threatening condition [4,5]. Early recognition and an understanding of the selection and timing of therapeutic options remain critical elements in the optimal management of patients with this disorder.
About Tracleer® in Pulmonary Arterial Hypertension (PAH) Tracleer® (bosentan), the first oral dual endothelin receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH) and made available by Actelion subsidiaries in the United States, the European Union, Japan, Australia, Canada, Switzerland and other markets worldwide.
About Tracleer® in Digital Ulcers (DU) DUs are a manifestation of the underlying vasculopathy which is central to the pathophysiology of systemic sclerosis (SSc) and pivotal in the development of PAH in SSc, one of the leading causes of death in SSc. Endothelin, a pathogenic mediator, is implicated in the underlying vasculopathy in SSc.
DUs can be a frequent, persistent and debilitating complication of SSc. They are caused by a reduction in the lumen of small bloody vessels that decreases blood flow to the fingers and toes causing open sores. DUs are painful, with a debilitating impact on patients' daily life, often making it impossible to work and undertake even simple day-to-day activities, particularly those associated with fingertip function. Reducing the occurrence of new DUs is an important and achievable treatment goal in SSc.
In the EU, Tracleer® is indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. Tracleer® has been shown to improve hand function (i.e. dressing and hygiene) in patients with scleroderma-induced digital ulcers.
Requires attention to two significant safety concerns : Potential for serious liver injury (including rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring) - Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter. High potential for major birth defects - Pregnancy must be excluded and prevented by two forms of birth control; monthly pregnancy tests should be obtained. Because of these risks, Tracleer® is only supplied through controlled distribution.
About macitentan Macitentan is a highly potent, tissue-targeting endothelin receptor antagonist discovered in an in-house research program. Through complete blockade of tissular endothelin, macitentan is expected to protect tissue from the damaging effect of elevated endothelin.
Macitentan is currently being investigated in the Phase III study SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome). This study is designed to evaluate the safety and efficacy of this highly potent tissue-targeting endothelin receptor antagonist through the primary endpoint of morbidity and all-cause mortality in patients with symptomatic PAH. Global enrollment was completed in December 2009 with a total of 742 patients.
Macitentan is also being investigated in a double-blind, randomized, multicenter exploratory study evaluating efficacy and safety in 150 patients with idiopathic pulmonary fibrosis.
1. King T.E. et al. et al. A Randomized Placebo-controlled Trial of Bosentan in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 177. pp 75-81, 2008 2. Tracleer® SPC 3. Farber HW; Loscalzo J. Mechanisms of disease: pulmonary arterial hypertension. N. Eng. J. Med. 2004; 351:1655-65. 4. Humbert M; Sitbon O; Simonneau G. Treatment of pulmonary arterial hypertension. N. Eng. J. Med. 2004;351:1425-36. 5. Humbert M; Morrell NW; Archer SL; et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2004; 43: Suppl. 12: 13S-24S.
Actelion Ltd Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer® through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia 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's over 2,200 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI® )
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Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
+1 646 737 49 72 http://www.actelion.com<http://www.actelion.com/>
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