Patients receiving Tracleertm
(bosentan), the first oral therapy for pulmonary hypertension (PHT),
demonstrated significant improvements in their exercise ability and
hemodynamics, according to results of a clinical trial presented today at the
American Heart Association 73rd Annual Scientific Session.
Pulmonary hypertension is a chronic life-threatening disease that cripples
the lungs and heart. The only currently approved therapy for PHT is
intravenous, complicated by administration difficulties and side effects. As
part of the ongoing search for a suitable oral therapy, investigators, led by
Lewis Rubin, MD, of the University of California at San Diego, have reported
significant results from the study: "Effects of the Dual Endothelin Receptor
Antagonist Bosentan in Patients with Pulmonary Hypertension."
Results Demonstrated Increase in Exercise Ability and Hemodynamics
At 12 weeks patients in the Tracleer group demonstrated a 20 percent
increase in exercise ability compared to placebo in the standardized
six-minute walk test (p=0.018). Tracleer patients improved their timed walk
distance by a mean of 72 meters. In addition, a highly significant (p less
than 0.0001) 40 percent net difference in cardiac output in favor of Tracleer,
compared to placebo, was observed.
Dr. Rubin stated, "The improvements were significant enough that
43 percent of patients (9 of 21) receiving Tracleer were reclassified as
'moderate'* from their previous 'severe' status, as compared to only 9 percent
of patients (1 of 11) receiving placebo. This double-blind,
placebo-controlled trial involved 32 patients. Though limited in patient
number, the findings are important and relevant considering the magnitude of
the clinical and hemodynamic responses which achieved statistical
The trial was sponsored by Actelion Pharmaceuticals, Ltd., developers of
Tracleer. The company has filed initial data with the U.S. Food and Drug
Administration and expects to complete the NDA filing for Tracleer for use in
patients with pulmonary hypertension by the end of November 2000.
"Endothelin receptor antagonism represents a totally new approach to
treating pulmonary hypertension," says chief executive officer and founder of
Actelion, Jean-Paul Clozel. "We believe that the oral dosing and therapeutic
advantages of Tracleer could represent a major breakthrough for the standard
of care in PHT."
Pulmonary hypertension is a life-threatening condition with a survival
rate in untreated patients of only 40 to 55 percent at two years from the
onset of symptoms.(1,2) Some studies estimate that approximately 100,000
people in the U.S. and Europe are afflicted with either primary PHT or
secondary forms of the disease related to conditions or tissue disorders that
affect the lungs; these include the use of appetite suppressants and diseases
such as scleroderma, portal hypertension and HIV/AIDS.
The study was conducted in six treatment centers, five in the U.S. and one
in France. All 32 patients were randomized to receive either a 62.5 mg bid
dose of Tracleer, which was doubled after four weeks to 125 mg bid, or
matching doses of placebo.
Results Show Improvement in Pulmonary Arterial Pressure
In addition to significantly improving the distance walked by patients,
Tracleer significantly decreased mean pulmonary artery pressure (p=0.013),
mean pulmonary vascular resistance (p less than 0.0001), mean pulmonary
capillary wedge pressure (p=0.035) and mean right atrial pressure
(p less than 0.0001), all of which worsened in the placebo group. The
hemodynamic improvements observed with Tracleer were not associated with
changes in heart rate, signifying that the functioning of the right side of
the heart improved without an increase in workload.
Tracleer was well-tolerated and the adverse events were transient and
similar in both type and frequency in each of the treatment groups. The most
common adverse event was headache. Asymptomatic elevations in liver enzymes
were observed in two patients in the treatment group, but these levels
normalized without discontinuation or change in the 125 mg bid dose of
Tracleer, the first orally active dual endothelin receptor antagonist,
blocks the action of endothelin at the ETA and ETB receptors and potentially
offers significant improvements to currently available PHT therapies.
Endothelin is the most potent vasoconstrictor known to date and appears to
play a fundamental mechanistic role in the development of PHT. Most of the
features of PHT, such as vascular hypertrophy, high pulmonary resistance and
secondary right heart hypertrophy, can be explained by the action of
Tracleer is also the focus of a larger phase III study. The Bosentan:
Randomized Trial of Endothelin Receptor Antagonist THErapy for Pulmonary
Hypertension (BREATHE-1) has already enrolled more than 100 of its planned
150 patients. The trial, initiated by Actelion, is part of a complete
research program in pulmonary hypertension.
* 'Moderate' is defined as Stage 2 functional class by the World Health
Organization; 'severe' is defined as Stage 3 functional class.
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Isolated pulmonary hypertension in systemic sclerosis with diffuse cutaneous
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