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ATS bosentan in combination with tadalafil

Evidence grows for multiple drug therapy use with Tracleer® (bosentan) as first line therapy

ALLSCHWIL, SWITZERLAND – 18 May 2009 – Patients with pulmonary arterial hypertension (PAH) who receive an additional 20 or 40mg tadalafil to their first-line bosentan therapy demonstrated a trend towards a positive 23m improvement during the six-minute walk distance (6MWD) test, a measure of symptom severity and functioning, according to the PHIRST study data [1] presented at the 2009 American Thoracic Society (ATS) conference today.

Professor Nazzareno Galié of the University of Bologna, Italy commented: “These data are interesting because this is the first time that the efficacy of an ERA and PDE-V inhibitor in combination has been indicated in a randomized clinical trial with a pre specified sub group analysis”

These findings are consistent with previous data investigating the impact of multiple drug therapy on symptoms, functioning and outcomes [2]. Tracleer® is the most widely studied PAH therapy with the addition of combination therapies including PDE5 inhibitors and inhaled, IV or oral prostacyclins.

Dr Sean Gaine, Head of the National Pulmonary Hypertension Centre, Dublin commented: “Many PAH patients are not diagnosed until their disease has progressed. This highlights the need for screening patients at risk, early diagnosis and treatment. We believe the goal of therapy should be to delay the deterioration of their condition and where possible maintain and even improve their ability to function at a level where the disease has less impact on their lives. If treatment goals are not being achieved on current therapy then the evidence suggests that a multiple medication approach should be used to achieve these goals.”

This view is reflected in the ACCF/AHA Expert Consensus Document on PH, which states that there is scientific rationale for the use of combination therapy with the goal of maximizing efficacy, while minimizing toxicity [3]. Treatment goals were highlighted as improving symptoms and enhancing functional capacity, as measured by the 6MWD test; maintaining or reversing disease progression and improving outcomes [3]. The consensus document states that, despite treatment, patients in FC III or IV have worse outcomes [3]. This view would appear to recognize the need to treat patients earlier in FC II before the condition has worsened.

Tracleer® is an oral dual endothelin receptor antagonist, which is currently licensed for the treatment of pulmonary arterial hypertension (WHO Group I), a chronic, life-threatening disorder which severely compromises the function of the lungs and heart. In the United States, Tracleer® is approved for treatment of PAH Functional Class III and IV to improve exercise capacity and decrease the rate of clinical worsening, and in Europe it is approved for treatment of PAH Functional Class III to improve exercise capacity and symptoms, as well as PAH Functional Class II where some improvements have also been shown. In the EU Tracleer® is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease. Regulatory review for the inclusion of functional class II in the Tracleer® label is ongoing on a worldwide basis. [4,5]


Notes to Editor:

About the study

Please see Reference 1 for more information on the study.

About the BREATHE-1 study (Bosentan Randomized trial of Endothelin Antagonist THErapy-1) [6]

The BREATHE-1 study, investigated 213 patients with severe PAH who were randomly assigned to receive either placebo or bosentan monotherapy. At week 16, patients treated with bosentan showed a significant improvement in 6MWD; the mean difference between the placebo group and the combined bosentan groups was 44m (95% Cl, 21 to 67; p<0.001).

About the EARLY trial (Endothelin Antagonist tRial in miLdlY symptomatic PAH) [7]

Results from the EARLY trial (Endothelin Antagonist tRial in miLdlY symptomatic PAH) gathered from a cohort of 185 patients have suggested that early treatment with bosentan is beneficial in PAH patients with mildly symptomatic WHO FC II.

About the COMPASS-1 / COMPASS-2 study

COMPASS-1[8] was the first clinical trial to provide detailed hemodynamic information on the combination of sildenafil and bosentan. Findings showed that the combination of sildenafil together with long-term bosentan therapy produces significant hemodynamic improvements including a highly significant reduction in mean PVR observed 60 minutes after administration of a single dose of sildenafil 25 mg (-15.2% [95% CI: –20.8 to –9.6]; p < 0.0001) and a decrease in the mean total pulmonary resistance (-13.3% [95% CI: –17.0 to –9.6]; p < 0.0001). COMPASS-2 is the continuation of this trial to explore the benefits in combination therapy vs monotherapy on exercise capacity.

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 [9] 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) [10]. 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 [10,11]. 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.

Requires attention to two significant safety concerns: [6] 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 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.


Barst RJ, et al. Prospective subgroup analyses of patients with and without background bosentan therapy from a phase 3 trial of tadalafil in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2009; 179:A3373.
Hoeper MM, et al. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005; 26:858-863
McLaughlin VV et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension, J. Am. Coll. Cardiol 2009; 53: No. 17 published online Mar 30, 2009.
Tracleer® SmPC.
Tracleer® Prescribing Information.
Galié N, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind randomized controlled study. Lancet 2008; 371: 2093-2100
Rubin LJ, et al. Bosentan therapy for pulmonary arterial hypertension. NEJM 2002; 346:896-903.
Gruenig E et al. Acute administration of sildenafil in patients with pulmonary arterial hypertension (PAH) treated with bosentan produced a significant hemodynamic response: results of the COMPASS-1 study. European Society of Cardiology (ESC) Congress 2007 Abstract 1012.
Farber HW; Loscalzo J. Mechanisms of disease: pulmonary arterial hypertension. N. Eng. J. Med. 2004; 351:1655-1665.
Humbert M, et al. Treatment of pulmonary arterial hypertension. N. Eng. J. Med. 2004; 351:1425-1436.
Humbert M, 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 2000 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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Posted: May 2009