-- 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. 17, 2006 (PRIME NEWSWIRE) -- Actelion Ltd (SWX:ATLN), (Other OTC:ALIOF) 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 Gerald Simonneau from the Hospital Antoine Beclere, 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 Galie, 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 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, December 18, 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 January 1, 2007 it will be stored under Investors/Past Events.
Actelion's calendar 2007
Date: Event:
February 22, 2007 Full year 2006 results,
Actelion Day - formal invitation
to follow in early January 2007
April 19, 2007 3-month 2007 financial results
July 19,2007 6-month 2007 financial results
October 18, 2007 9-month 2007 financial results