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Back To Vidyya Postive Results For First Oral Therapy For Pulmonary Hypertension In Phase III Trial

Tracleertm (Bosentan) Demonstrates Significant Improvements In Exercise Ability And Hemodynamics

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 significance."

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.

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 endothelin.

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.

1. Stupi AM, Steen VD, Owens GR, Barnes EL, Rodnan GP, Medsger TA, Jr. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 1986; 29:515-24.

2. Sacks DG, Okano Y, Steen VD, Curtiss E, Shapiro LS, Medsger TA, Jr. Isolated pulmonary hypertension in systemic sclerosis with diffuse cutaneous involvement: association with serum anti-U3RNP antibody. J Rheumatol 1996; 23:639-42.

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Editor: Susan K. Boyer, RN
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