ALLSSHWIL, Switzerland, Sept. 02, 2003 (PRIMEZONE) -- Actelion Ltd (SWX:ATLN) (Other OTC:ALIOF) today announced results of a study assessing its oral dual endothelin receptor antagonist (ERA) Tracleer(R) (bosentan) in the treatment of pulmonary arterial hypertension (PAH) related to HIV (human immunodeficiency virus) infection.
Analysis of this open-label study showed a statistically significant improvement in hemodynamic parameters, exercise capacity (6-minute walk test), functional status and quality of life compared to baseline after 16 weeks of treatment with Tracleer(R). The results also indicate that Tracleer(R) can be given together with antiretroviral therapy and is well tolerated.
Study results were presented today at the European Society of Cardiology (ESC) meeting in Vienna by Dr. Olivier Sitbon from the Center of Pulmonary Vascular Diseases at the Hopital Antoine Beclere in Clamart, France.
Dr. Sitbon commented that: "This supportive trial provides useful and important information on the use of Tracleer(R) in patients, controlled for HIV infection. I am very pleased that the trial demonstrates that the treatment has a positive impact on the quality of life of these PAH patients."
Tracleer(R) is currently approved and available in the United States, the European Union, Canada, Australia, Israel and Switzerland for the treatment of Pulmonary Arterial Hypertension (PAH).
About the study design of BREATHE-4
In the multicenter, multinational, open-label, non-comparative, phase IIIb trial BREATHE-4 (Bosentan Randomized trial of Endothelin Antagonist THErapy for Pulmonary Hypertension-4), the safety and efficacy of Tracleer(R) (bosentan) was evaluated over a time period of 16 weeks in 16 patients with PAH related to HIV infection. The initial sample size was 30 patients, but enrollment was concluded early as the positive results observed were felt by the investigators to be of clinical relevance and merit immediate reporting. Efficacy was measured as change in hemodynamics, exercise capacity (6-minute walk test), clinical worsening and WHO functional class compared to baseline. Safety was evaluated, using standard safety assessments (liver function tests) with additional routine evaluation of HIV status (CD4 cell count and viral load).
BREATHE-4 study results
At week 16, highly significant improvements in cardiac index and pulmonary vascular resistance were seen (p less than 0.001). These hemodynamic changes translated into improvement in right ventricular geometry and function as assessed by Doppler echocardiography.
The 6-minute walk distance increased by 91 meters (highly significantly, p less than 0.001), from 333 (+/-79) meters at baseline to 424 (+/-57) meters at week 16. NYHA class improved for 14 patients after 16 weeks of Tracleer(R) treatment. No patient died and none required epoprostenol or hospitalization for PAH. There were no concerns that bosentan affected virological control of HIV infection.
Deterioration in quality of life (QoL) caused by PAH in HIV patients was ameliorated substantially by Tracleer(R) therapy, particularly in the area of physical health. Physical functioning (p less than 0.001), general health (p less than 0.001) and vitality (p=0.002) as well as mental health and social functioning scores improved significantly.
About Pulmonary Arterial Hypertension (PAH)
Around 100,000 people in Europe and the US currently suffer from pulmonary arterial hypertension, which includes PPH or PAH related to other diseases such as scleroderma, a degenerative connective tissue disease (1) or HIV. Early diagnosis is important for PAH patients. Unfortunately, diagnosis can often be delayed because initial symptoms are unspecific (i.e. breathlessness) and therefore go undetected or are attributed to other diseases.
About PAH in HIV infection
PAH is a severe complication of human immunodeficiency virus (HIV) infection. PAH occurs in approximately 0.5% of all HIV-infected patients and contributes significantly to morbidity and mortality. Similarly to cases of PPH, progressive shortness of breath, especially upon exertion, is the most common presenting symptom. These patients very rarely respond to acute vasodilation testing.
Most of the HIV patients fall into World Health Organization (WHO) functional class III to IV (moderate to severe) by the time they are diagnosed with PAH (2). It has been hypothesized that HIV is implicated in endothelial dysfunction and mediates vasoconstriction by stimulation of endothelin release (3). The development of PAH in HIV patients has been shown to be a significant independent predictor of death and to reduce the probability of survival in HIV patient by half (median survival is 1.3 years from diagnosis vs. 2.6 years without PAH (4)).
Tracleer(R) in PAH -- Pivotal studies Tracleer(R), the first oral dual endothelin receptor antagonist, has demonstrated its efficacy in two pivotal, placebo-controlled studies (1,5). Tracleer(R) has shown statistically significant improvements in the primary efficacy endpoint of exercise capacity with patients achieving a significantly greater, and clinically meaningful increase in walking distance compared to placebo.
Pivotal clinical trials have also demonstrated Tracleer(R)'s efficacy in significantly decreasing dyspnea (shortness of breath), one of the most debilitating symptoms for people with PAH. Additionally, treatment with Tracleer(R) is also associated with a significant the time to clinical worsening (5). Clinical worsening is defined as combined endpoint of death, hospitalization or discontinuation due to worsening PAH, or initiation of epoprostenol therapy.
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; who do not use a reliable method of contraception, must not take Tracleer(R).
Tracleer(R) in PAH -- Supportive studies and supportive long-term follow-up
In several supportive follow-up studies, Actelion has continued to further profile Tracleer(R) in PAH. BREATHE-2 investigated the combination of Tracleer(R) with initiation of epoprostenol i.v. in adult PAH patients (6). BREATHE-3 evaluated the treatment of children with PAH with Tracleer(R) alone an in combination with epoprostenol (7). In order to assess potential long-term outcome improvements with first-line Tracleer(R) treatment in PAH, Actelion analyzed long-term follow-up data of 169 patients previously enrolled in two pivotal studies, who had at that time of enrollment, a diagnosis of primary pulmonary hypertension (8).
Actelion Ltd Actelion Ltd is a biopharmaceutical company with its corporate headquarter 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 as well as Canada 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 focuses 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
NOTE TO THE EDITOR: Please note that Actelion will release its Q3 results on Tuesday 28 October 2003 and will hold a Research and Development day on 29 October 2003 (London) and on 30 October 2003 (New York).
Conference Call
Dr. Olivier Sitbon has agreed to make his ESC presentation also available through an Actelion-sponsored conference call and webcast. The webcast is taking place on Tuesday, 2 September 2003, 03.30 p.m. (CET) / 09.30 a.m. (EST) / 02.30 p.m. (GMT) Dial: +41 (0) 91 610 56 00 (Europe) +1 412 858-4600 (U.S.) +44 207 107 0611 (U.K.)
Webcast -- Live and replay on demand To follow Dr. Sitbon's presentation live or to have the call replayed later on demand, simply visit the link on our homepage http://www.actelion.com.
(1) Channick R et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo controlled study. Lancet 2001; 358:1119-23
(2) Nunes H, Humbert M, Sitbon O, et al. Prognostic factors for survival in human immuno deficiency virus associated-pulmonary arterial hypertension. Am J Respir Crit Care Med 2003; 167:1433-1439.
(3) Mehta NJ, Khan IA, Mehta RN, Sepkowitz DA. HIV-related pulmonary hypertension. Analytic review of 131 cases. Chest 2000; 118:1133-1141.
(4) Opravil M, Pechere M, Speich R, Joller-Jemelka HI, Jenni R, Russi EW, et al. HIV-associated primary pulmonary hypertension. A case control study. Am J Respir Crit Care Med 1997; 155:990-995.
(5) Rubin LJ, Badesch DB, Barst RJ, Galie N, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002:346:896-903.
(6) Humbert M, Barst RJ et al. Safety and efficacy of bosentan combined with epoprostenol in patients with severe pulmonary arterial hypertension. Am J Resp. Crit. Care Med 2003; 167(7), A441
(7) Barst RJ, Dunbar I et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003; 73:372-82.
(8) McLaughlin V, Sitbon O, Rubin LJ et al. The effect of first-line bosentan on survival of patients with primary pulmonary hypertension. Abstract presented at American Thoracic Society, 2003.