Actelion Announces Successful Study with Tracleer in Patients with Mildly Symptomatic Pulmonary Arterial Hypertension

Significant Reduction in Pulmonary Vascular Resistance - Strong Trend Towards Improvement in Exercise Capacity - Significant Delay in Time to Clinical Worsening - Full Data Analysis Ongoing in View of Upcoming Regulatory Filing Seeking Expansion of the Indication   

ALLSCHWIL, Switzerland, Dec. 18, 2007 /CNW Telbec/ - Actelion Ltd (SWX: ATLN)  announced today that initial results from the double-blind,  placebo-controlled, multicenter study EARLY (Endothelin Antagonist Trial in  mildly Symptomatic PAH patients, NYHA modified functional class II) indicate that six months of treatment with the dual endothelin receptor antagonist  bosentan (Tracleer(R)) showed a significant reduction in pulmonary vascular  resistance, a strong trend towards improved exercise capacity and a  significant delay in the time to clinical worsening.  

Isaac Kobrin, MD and Head of Development of Actelion, commented: "I am  very pleased that now for the third time in a double-blind, placebo-controlled  PAH trial, Tracleer(R) has shown a significant delay in time to clinical  worsening, and this time in patients that presented at baseline with mild  symptoms and, on average, relatively well preserved exercise capacity. Also,  in this population, we observe a significant reduction in pulmonary vascular  resistance; a measurement gained by a direct invasive procedure and considered  to be a robust indicator of disease severity."   

Unique properties of dual ERA Tracleer(R) in PAH   

Treatment with Tracleer(R) in 185 mildly symptomatic PAH patients (NYHA  modified functional class II) was associated with a highly significant  reduction in pulmonary vascular resistance (PVR) compared to placebo (p(less  than)0.0001), a primary endpoint of the study. Patients on Tracleer(R) also  showed a strong trend towards improvement in 6-minute-walk test compared to  placebo (p=0.076, ns), another primary endpoint. The study met its main  secondary endpoint, as treatment with Tracleer(R) was associated with a  significant delay in time to clinical worsening compared to placebo (p=0.018),  representing a 70 percent reduction in risk.      

In this study, Tracleer(R)'s safety and tolerability profile was  consistent with that observed in previous placebo-controlled clinical trials.       The company will now fully analyze the data in anticipation of planned  upcoming regulatory filings worldwide to expand the Tracleer(R) indication to  include mildly symptomatic PAH patients (NYHA modified functional class II).  Tracleer(R) - first approved in the United States in late 2001 for PAH  patients with NYHA modified functional class III and IV - is already available  in all major pharmaceutical markets worldwide.      

Dr. Kobrin concluded: "Currently, regulatory approval of PAH drugs  focuses on significant symptomatic changes. In this study where patients  presented on average with well-preserved exercise capacity at baseline, the  six-minute-walk test nevertheless showed a strong trend towards significance.  More importantly, Tracleer(R) has consistently demonstrated its unique ability  to delay time to clinical worsening, the ultimate treatment goal."      

Jean-Paul Clozel, MD and Chief Executive Officer: "Actelion has always  been at the forefront to expand knowledge and treatment options in PAH. The  EARLY study once again contributes to a better understanding of the disease  and demonstrates the clear need for early intervention. In addition, this  study highlights our outstanding leadership in PAH with Tracleer(R) the  treatment of choice. In addition, we provide an unparalleled number of  positive datasets that assist physicians in making appropriate treatment  decisions."    

Disease awareness, early diagnosis and early intervention expected to increase   

Professor Gérald Simonneau from the Hospital Antoine Béclère, Clamart,  Paris/France and a member of the EARLY steering committee, commented: "This is  the first study specifically evaluating treatment effects in early stages of  PAH. The results of this study teach us that without targeted treatment, also  mildly symptomatic PAH patients will relentlessly deteriorate within a short  period of time. Such clinical worsening was significantly delayed when  patients received treatment with Tracleer(R)."      

Professor Lewis J. Rubin, University of California, San Diego, La  Jolla/USA and a member of the EARLY steering committee, added: "These findings  with Tracleer(R) univocally highlight the need for early diagnosis and  intervention to provide patients with PAH with best medical care as early as  possible to have an impact on delay in time to clinical worsening.  Accordingly, I believe that these study results will further support the  ongoing outreach to the medical community to increase disease awareness,  result in earlier diagnoses and provide treating physicians with clear  treatment guidelines."      

Professor Marius Hoeper, Medizinische Hochschule, Hannover/Germany and a  member of the EARLY steering committee, commented: "This is an exciting study  since it shows for the first time that it is possible to slow the progression  of PAH at early stages with appropriate medical therapy."      

Professor Nazzareno Galiè, Istituto di Cardiologia, University of  Bologna/Italy and a member of the EARLY steering committee, commented: "The  results of the EARLY study inform us about the way future clinical studies in  PAH should be conducted. With more patients now diagnosed earlier and more  patients receiving multiple agents from different classes of PAH therapies, we  must now move beyond the six-minute-walk test as our standard assessment tool  and move towards the more reliable evaluation of delay in time to clinical  worsening."  

About the EARLY study design   

The Phase IIIb study EARLY (Endothelin Antagonist Trial in Mildly  Symptomatic PAH patients) enrolled a total of 185 PAH patients (92 on placebo  and 93 on bosentan) in 52 centers in 22 countries (United States, Europe,  Middle East, Latin America, Australia and South-East Asia). EARLY was a  double-blind, placebo-controlled study, which enrolled male and female  patients aged 12 and over with mildly symptomatic (modified NYHA functional  class II) PAH. Strict inclusion and exclusion criteria were applied to ensure  that only mildly symptomatic patients were enrolled and the PAH status was  confirmed by invasive hemodynamic assessment at baseline.      

The regimen for bosentan was an initial dose of 62.5 mg b.i.d. for four  weeks for all patients and a target dose of 125 mg b.i.d. for five months for  an overall exposure to either active study drug or placebo of six months.  After six months, patients could opt to continue in an open-label extension  study that is currently still ongoing and is expected to yield long-term data.      

The primary objective of the study was to demonstrate that bosentan  improves cardiac hemodynamics and, as subordinate, exercise capacity in mildly  symptomatic PAH patients. The main secondary objective of the study was the  evaluation of the effect of bosentan on time to clinical worsening. Other  secondary objectives included dyspnea, NYHA Class and quality of life. The  study also evaluated safety and tolerability.      

After the approval of sildenafil as a PAH treatment option, Actelion  amended the EARLY trial design to include sildenafil as background therapy.  The analysis of the pre-defined stratum of 28 sildenafil patients who where  randomized to either receive placebo or bosentan will become available at a  later time.   

About Tracleer(R) in Pulmonary Arterial Hypertension (PAH)   

Tracleer(R) (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.      

In clinical trials leading to the marketing approval of the drug,  approximately 11% of PAH patients receiving Tracleer(R) 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(R).    

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.   

About bosentan in clinical development for PAH   

Actelion aims to develop products to their maximum potential by  implementing comprehensive strategies of line extensions and new indications.  Since gaining approval of Tracleer(R) in 2001, Actelion has continued to  invest in further clinical trials to expand its use. In many territories,  regulatory review either has been successfully concluded (Europe, Canada) or  is ongoing regarding the inclusion of data from BREATHE-4 and BREATHE-5  studies that included patients with PAH associated with HIV and PAH associated  with congenital heart disease (CHD) respectively.      

Several trials are currently underway to expand the bosentan treatment to  pediatric PAH patients (FUTURE-1), and in combination with sildenafil in PAH  patients (COMPASS-1/-2). In addition, bosentan is evaluated in additional  forms of PAH, such as chronic thrombo-embolic pulmonary hypertension (BENEFIT)  and, pulmonary hypertension secondary to sickle cell disease (ASSET-1/-2)   

Actelion Ltd   

Actelion Ltd. is a biopharmaceutical company with its corporate  headquarters in Allschwil/Basel, Switzerland. Actelion's first drug  Tracleer(R), an orally available dual endothelin receptor antagonist, has been  approved as a therapy for pulmonary arterial hypertension. Actelion markets  Tracleer(R) 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(R)  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).   

Conference Call   

Actelion will host an Investor Conference Call and discussion/Q&A on  Monday, 18 December 2006, 08.00 CET / 07.00 GMT / 02.00 a.m. EST   

Dial:  +41 (0) 91 610 56 00  (Europe)              +1 (1) 866 291 41 66  (U.S.)              +44 (0) 207 107 06 11  (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.  Approximately 60 minutes after the call has ended, the archived investor  webcast will be available for replay through our homepage. After 1 January  2007 it will be stored under Investors/Past Events.   

For further information: 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/ 

Posted: January 2007

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