Pivotal Pulmonary Arterial Hypertension Study Concludes That Early Detection and Intervention is Key to Delay Disease Progression: Financial News

Pivotal Pulmonary Arterial Hypertension Study Concludes That Early Detection and Intervention is Key to Delay Disease Progression
Tuesday September 23, 2008 7:00 am ET

LAVAL, QUEBEC--(MARKET WIRE)--Sep 23, 2008 -- Actelion Pharmaceuticals Canada announced today that data presented at the recent European Cardiology Society meeting, and also published in The Lancet(1) show that, even in mildly symptomatic pulmonary arterial hypertension (PAH) patients (WHO functional class II - WHO FC II), the disease progresses very rapidly, such that patients can worsen to the most severe, WHO functional class III and IV in a short period of time. The randomized, placebo-controlled EARLY (Endothelin Antagonist tRial in miLdlY symptomatic PAH patients) trial is the first and only clinical trial conducted exclusively in a specifically dedicated WHO FC II PAH patient population.

Dr. Sanjay Mehta, Associate Professor of Medicine at the University of Western Ontario and Director, Southwest Ontario Pulmonary Hypertension Clinic, London Health Sciences Centre, commented: "The results from EARLY highlight/emphasize the relentlessly progressive nature of PAH, even in its early stages. It is of paramount importance to screen high risk patients to diagnose PAH in a timely fashion. It is also crucial that all PAH patients, regardless of functional class, be closely monitored for the earliest signs and symptoms of PAH progression and that treatment of all symptomatic PAH patients be considered to prevent PAH progression and worsening."

The objectives of the EARLY trial were to investigate the effects of bosentan specifically in PAH patients in WHO FC II and to gain more insight into early stage disease. The co-primary endpoints were changes in pulmonary vascular resistance (PVR) and exercise capacity (6MWD). Disease progression was assessed by the secondary endpoints time to clinical worsening and WHO functional class.

The findings of EARLY indicate that treatment with bosentan may be beneficial for WHO FC II PAH patients. In EARLY, bosentan (Tracleer®) prevented clinical deterioration by significantly delaying time to clinical worsening and reduced the number of patients worsening to WHO FC III/IV. A significant reduction in pulmonary vascular resistance and a positive trend in increasing the 6MWD were also observed.

A highly significant reduction in PVR of 22.6% (p less than 0.0001) and a significant 77% risk reduction in delaying the time to clinical worsening (p equals 0.011) were seen after six months of bosentan treatment compared with placebo. Time to clinical worsening, defined by death, hospitalization for PAH and symptomatic progression of PAH, showed that more patients remained stable without signs of deterioration in the bosentan-treated group compared with placebo (3.4% vs. 13.2%, p equals 0.029). In addition, a significant delay in WHO functional class deterioration was observed in the bosentan group compared with placebo, providing further evidence of delayed disease progression. The improvement in 6MWD did not reach statistical significance (p equals 0.076). This may reflect the fact that, on average, patients in EARLY had a relatively well-preserved exercise capacity, which therefore can be difficult to further improve.

The safety and tolerability profile of bosentan was consistent with that observed in previous placebo-controlled clinical trials(2),(3).

Dr. Mehta commented: "The EARLY trial clearly demonstrates that without treatment, even mildly symptomatic patients experience PAH progression within a short period of time. In order to properly delay the progression of PAH and increase patients' chances of survival, it is imperative to diagnose patients in the early stages of their disease cycle, ideally WHO functional class II, and treat them with an evidence-based approach as soon as possible."

EARLY is the third randomized controlled trial with bosentan, to provide data that show a consistent significant effect on delaying PAH progression and reducing disease severity. The data from the other two pivotal trials, Study 351(2) and BREATHE-1(3) trial, which both investigated bosentan in FC III and IV patients, were published in The Lancet and the New England Journal of Medicine respectively.

A subgroup of patients who received concomitant sildenafil showed improvements in PVR and 6MWD consistent with the overall results.

Further evidence of the effect of bosentan on hemodynamics is provided by the reduction of NT-proBNP plasma concentration in the bosentan-treated group compared to the increase in the placebo-treated patients. It is generally considered that a decrease in plasma concentration of NT-proBNP following targeted PAH therapy is a predictive factor for patient outcome.

An open-label extension of EARLY is ongoing to establish the impact of early intervention on long-term patient outcome.

Notes to editor

About Pulmonary Arterial Hypertension (PAH)

PAH is a syndrome characterized by a progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular failure and premature death(4). If untreated, PAH carries a very poor prognosis with a median survival of 2.8 years after diagnosis(5).

There are four WHO functional classes for PAH with class I being the least severe and class IV being the most advanced. These reflect the impact of PAH on a patient's life in terms of symptoms and ability to tolerate physical activity. Class II patients are defined as patients with pulmonary hypertension resulting in mild limitation of physical activity, such that they are comfortable at rest but ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope(6).

The pathogenesis of PAH involves the increased production of vasoactive compounds, such as endothelin. Endothelin is produced by the endothelial cells and is essential for maintenance of normal vascular tone and function. Tracleer® was the first in a new class of treatments for PAH known as endothelin receptor antagonists. Tracleer® is a dual antagonist as it blocks both ETA and ETB receptors preventing the deleterious effects of endothelin.

It is estimated that PAH affects somewhere in between 2,000 and 10,000 Canadians, with approximately 500 new cases diagnosed each year. PAH knows no boundaries affecting children, women and men of all ethnicities and ages. Symptoms of PAH include persistent, unexplained shortness of breath, chest pain, fatigue, intolerance to exercise, dizziness, fainting and swollen feet and /or ankles.

About Tracleer® in Pulmonary Arterial Hypertension (PAH)

Tracleer® is an oral dual endothelin receptor antagonist, which is currently approved in Canada for the treatment of PAH in patients with WHO functional class III or IV primary pulmonary hypertension, or pulmonary hypertension secondary to scleroderma or congenital heart disease or human immunodeficiency virus in patients who did not respond adequately to conventional therapy.

Actelion also conducted clinical trials to further describe the role of bosentan in treating PAH in specific patient populations, such as patients with congenital heart disease (with Eisenmenger syndrome; BREATHE-5), patients infected with HIV (BREATHE-4). Study results are reflected in the Tracleer® product monograph. A clinical study with bosentan in children suffering from PAH (BREATHE-3) has resulted in the ongoing clinical evaluation of a specific children formulation of bosentan.

Tracleer® has been made commercially available by Actelion subsidiaries in the United States, the European Union, Japan, Australia, Canada, Switzerland and other markets worldwide since 2001. In these six years of clinical experience, more than 50,000 patients have been treated with Tracleer®.

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 are recommended.

References

1. Galie N, Rubin LJ, Hoeper MM et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. The Lancet 2008; 371: 2093-2100.

2. Channick RN, Simonneau G, Sitbon O et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. The Lancet 2001; 358: 1119-23 (Study 351).

3. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. NEJM 2002; 346: 896-903 (BREATHE-1).

4. Sitbon O, Humbert M, Jais X et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111: 3105-3111

5. D'Alonzo GE, Barst RJ, Ayres SM et al. Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med 1991; 115: 343-349.

6. Barst RJ, McGoon M, Torbicki A et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43(Suppl S): 40S-47S

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 1700 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).