First-Ever Placebo-controlled Study in Inoperable Chronic Thromboembolic Pulmonary Hypertension - Primary Endpoint of Reduction in Pulmonary Vascular Resistance Met - Six-Minute-walk Test Unchanged - Significant Effect on Dyspnoea Score and Biological Disease Marker
ALLSCHWIL, Switzerland, March 5, 2007 -Actelion Ltd (SWX: ATLN) announced today the initial results from the double-blind, placebo-controlled, multicenter study BENEFiT (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension). The study met its primary objective, as treatment with bosentan (Tracleer) was associated with a significant reduction in pulmonary vascular resistance PVR (p<0.0001). In this first-ever double-blind study in a patient population suffering from this form of pulmonary hypertension, the six-minute walk test remained stable over the four months of blinded evaluation in both treatment groups. Patients on bosentan showed a significant improvement in breathlessness (Borg dyspnoea score) with exercise and there was a trend in favor of bosentan towards prevention of worsening WHO functional class. Initial results also indicate that treatment with bosentan was associated with a significant decrease in NT-proBNP, an important biomarker of disease severity. In this study, Tracleer ®'s safety and tolerability profile was consistent with that observed in previous placebo-controlled clinical trials in pulmonary arterial hypertension (PAH).
Isaac Kobrin, MD and Head of Development at Actelion, commented: "With the BENEFiT study, Actelion has leveraged its leadership in pulmonary arterial hypertension to conduct the first randomized, placebo-controlled study in a specific form of pulmonary hypertension. For patients with inoperable CTEPH, there are currently no approved therapies available. Now, our dual endothelin receptor antagonist bosentan has shown in this patient population signi ficant improvements in hemodynamic parameters that suggest positive patient benefits, as demonstrated by the significant improvements in breathlessness during exercise. Accordingly, we will discuss these findings with healthcare authorities worldwide."
Professor Lewis J. Rubin, University of California, San Diego, La Jolla/USA and a member of the BENEFiT steering committee added: "This first randomized placebo-controlled study in this inoperable patient population gives us a clear understanding how to improve medical care for these patients that are otherwise left without any options. Significant improvements in PVR and shortness of breath at exercise are matched by a significant decrease in NT-proBNP, an indicator of disease severity.
This study, therefore, also helps us in further advancing our understanding of both the disease and the appropriate way to evaluate therapeutic agents in pulmonary hypertension." Professor Gérald Simonneau, from the Hôpital Antoine Béclère, Paris, and lead investigator of the study commented: "For the BENEFiT study, we have chosen the pulmonary vascular resistance as primary objective as we use this key hemodynamic parameter to guide us in our daily medical management of CTEPH patients. Bosentan has now demonstrated a significant impact on this important parameter. Accordingly, bosentan might offer a new therapeutic option in these patients who cannot undergo surgery." CTEPH and bosentan (Tracleer®) findings in BENEFiT CTEPH is caused by obstruction of the pulmonary arteries by organized persistent thrombi leading to increased pulmonary vascular resistance, progressive pulmonary hypertension and ultimately right-heart failure. Pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH for suitable patients.
Nevertheless, up to half of all CTEPH patients cannot undergo surgery due to the nature of the disease and the location of the thrombi 1. Following surgery, 10-15% of pat ients may still have persistent or recurrent pulmonary hypertension 2. New treatment options are therefore required for both patient groups. Latest estimates put the number of new CTEPH patients at up to 5000 annually. In the 157 patient study BENEFiT, treatment with bosentan was associated with a highly significant reduction in pulmonary vascular resistance (PVR) compared to placebo (p<0.0001) and increase in cardiac index (p=0.0007). Borg dyspnoea index was also significantly improved (p=0.0386) and there was a trend in favor of bosentan towards prevention of worsening functional WHO class (p=0.1682, ns). Treatment with bosentan was also associated with a significant decrease in NT-proBNP (p = 0.0028), an important biomarker of disease severity. Other clinical parameters, such as time to clinical worsening and quality of life were consistently trending in favor of bosentan. Tracleer®'s safety and tolerability profile was consistent with that observed in previous placebo-controlled clinical trials in pulmonary arterial hypertension (PAH) 3. Upon complete data analysis, Actelion will present study results at upcoming scientific conferences, such as at the American Thoracic Society (ATS) meeting in San Francisco in May. BENEFiT study design in detail The BENEFiT (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension) study is the first double blind, randomized, placebo-controlled, parallel-group study in CTEPH patients. BENEFiT enrolled 157 patients in 26 centers in 13 countries. The mean age of patients enrolled in the study was 63 years and 65% of patients were female. Patients had either inoperable CTEPH or persistent or recurrent Pulmonary Hypertension after PEA (at least 6 months after hospital discharge).
The regimen for bosentan was 62.5mg bid for the first 4 weeks of treatment, increasing to 125mg bid for the following 12 weeks of the study. The primary objective of the study was to prove the efficacy of bosentan, wh en compared to placebo, on either one of the two primary endpoints, change in pulmonary vascular resistance (PVR) and/or exercise capacity measured by six-minute walk distance after 16 weeks of treatment. The statistical analysis plan stipulated that, if either endpoint was significant, the study was to be considered positive. Other endpoints included change from baseline to week 16 in other hemodynamic parameters, Borg dyspnoea, WHO functional class, time to clinical worsening, NT-proBNP as well as quality of life assessments.
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 4. In clinical trials leading to the marketing approval of the drug, approximately 11% of PAH patients receiving Tracleer® experienced abnormal but reversible liver enzyme elevations. It is therefore important that patients undergo monthly liver monitoring. Due to the risk of birth defects, women who are pregnant, or of childbearing age that do not use a reliable method of contraception, must not take Tracleer® 4. Online information on pulmonary arterial hypertension (PAH): www.pah-info.com As part of an international PAH awareness campaign supported by Actelion Pharmaceuticals, www.pah-info.com has been created to provide healthcare professionals and patients with accurate and continuously updated information on PAH. The website contains information on symptoms, causes, diagnosis and current treatment options in separate sections for healthcare professionals and patients. The website is supported by high-quality resources such as a glossary, links to an extensiv e list of worldwide patient associations and professional health organizations and additional sources of information.
References 1. Nick H & Kim S. Assessment of Operability in Chronic Thromboembolic Pulmonary Hypertension. Proc AmThorac Soc 2006; 3: 584-588 2. Dartevelle P et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004; 23:637-648. 3. LJ Rubin et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002; 346: 896-903 4. Tracleer® SPC 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. At the end of September 2006, Tracleer® was commercially available in 35 countries worldwide. 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 1,200 employees focus 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). For further information please contact: Actelion Ltd, Gewerbestrasse 16, CH-4123 Allschwil Investor Contact Roland Haefeli +41 61 565 64 58 +1 650 624 6936 Media Contact Peter Engel +41 61 565 66 28 +1 650 624 6996 http://www.actelion.com Conference Call Actelion will host an Investor Conference Call and discussion/Q&A on Monday, 5 March 2007, 07.45 CET / 01.45 AM EST / 06.45 GMT Dial: +41 (0)91 610 56 00 (Europe) +1 (1) 866 291 4166 (U.S. ) +44 (0) 207 107 0611 (U.K.) Webcast - Live and replay on demand Actelion webcasts its Investor Conference Call. On the Web, you may either follow the call live or have the call replayed later on demand. To access the webcast live, simply visit the link on our homepage http://www.actelion.com/ 5-10 minutes before the conference is due to start, or copy the following link into your browser: http://gaia.world-television.com/actelion/20070305/trunc/ Approximately 60 minutes after the call has ended, the archived investor webcast will be available for replay through our homepage. After 19 March 2007, it will be stored under Investors/Past Events