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
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.