First Oral Treatment of Pulmonary Arterial Hypertension Approved by the FDA

The U.S. Food and Drug Administration (FDA) approved Tracleer™ (bosentan), an orally active endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension (PAH) on November 20, 2001.  Tracleer is indicated to improve exercise ability and decrease the rate of clinical worsening in PAH patients with significantly limited physical activity.  PAH is a chronic, life-threatening disorder that can severely compromise the function of the lungs and heart.

Tracleer represents a medical research breakthrough.  It is the first agent to be approved by the FDA from a new class of drugs called endothelin receptor antagonists (ERAs).  Levels of endothelin, a potent blood vessel constrictor, are elevated in the plasma and lung tissue of patients with PAH, suggesting a pathogenic role for endothelin in the progression of this condition. Tracleer works by blocking the binding of endothelin to its receptors, thereby preventing the deleterious effects of endothelin upon blood vessels. Prior to the availability of this oral medication, the only approved treatment required an indwelling central intravenous line and patients had to carry a continuous infusion pump with them at all times.

Approximately 11 % of patients receiving Tracleer 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 may become pregnant, cannot take Tracleer.

Tracleer may be prescribed only through the Tracleer™ Access Program by calling 1-866-228-3546.

Clinical Background

The FDA approval is based on two successfully concluded pivotal trials, the larger of which is known as the BREATHE-1 (Bosentan: Randomized Trial of Endothelin Receptor Antagonist THErapy) trial. In this 213-patient trial, twice-daily Tracleer (125 mg b.i.d. and 250 mg b.i.d.) demonstrated, in both primary and secondary PAH, statistically significant improvements versus placebo in the primary efficacy endpoint of the study, which was exercise capacity. The overall treatment effect for both doses of Tracleer combined was a 44-meter improvement in walking distance as measured by a six-minute walk test, compared to placebo.  This improvement was maintained for up to seven months.  Treatment with Tracleer was also associated with a significant delay in the time to clinical worsening (death, hospitalization, worsening PAH or initiation of intravenous therapy) and with significant improvement in functional status and breathlessness.

What is PAH?

Approximately 100,000 people in the U.S. and Europe are afflicted with either primary pulmonary arterial hypertension or secondary forms of the disease related to conditions or tissue disorders that affect the lungs, such as scleroderma, lupus, HIV/AIDS, congenital heart disease or the use of certain appetite suppressants.

The first signs of the disease, such as mild shortness of breath, fatigue and difficulty exercising, are so subtle that the disease is often either misdiagnosed or not diagnosed until the patient's condition is far advanced. The survival rate for PAH in untreated patients is only 40 to 55 percent at two years from the onset of symptoms.  Once patients reach more advanced stages of PAH, they often have no choice but to go on prostacyclin therapy, which requires a 24-hour infusion pump and an intravenous line implanted through the chest directly into the patient's heart.  Ultimately, many patients require lung transplantation.

Tracleer 125mg, taken twice a day, is the first approved oral treatment for patients suffering from PAH.  Regulatory reviews are ongoing in the European Union, Canada, Switzerland and Australia. Tracleer has been granted Orphan Drug status in the US in pulmonary arterial hypertension. The company is currently studying Tracleer for children under the age of 12 suffering from PAH, as well as the concomitant use of Tracleer in patients who receive intravenous prostacyclin therapy.  Tracleer is currently also in Phase III trials to investigate its potential as a possible treatment of chronic heart failure (CHF).

Created: 12/26/2001  -  Donnica Moore, M.D.