A first-of-its-kind oral drug has been shown to successfully treat primary pulmonary hypertension (PPH), according to the results of a multi-center trial led by UCSD School of Medicine pulmonary specialists. Not only does the drug, bosentan, reverse the deadly consequences of PPH, which affects thousands of people, but also greatly improves patients’ quality of life.
The results, published in the Oct. 6 issue of The Lancet, suggest that bosentan can increase the exercise capacity of people suffering from the debilitating effects of PPH as well as improve their heart function and reduce other symptoms. By the end of the 12-week study period study participants on the drug increased their walking distance, in a standard six-minute walk, by 70 meters while those on the placebo decreased their distance by six meters. Limited activity and heart function are among the major setbacks for people with PPH, estimated to affect one to two patients per million, or 300 new cases per year.
PPH is a progressive narrowing of the small blood vessels in the lungs (the pulmonary arteries), which leads to enlargement and failure of the right ventricle of the heart, said Richard Channick, M.D., UCSD associate clinical professor of medicine, and lead author on the study. If left untreated, it usually results in death. Along with the death sentence, PPH greatly alters patients’ lives, according to Channick. Minor activities can leave patients breathless, and the most reliable current treatment for PPH patients requires continuous intravenous drug administration. The survival rate for a PPH patient after diagnosis is about three years.
The causes of PPH are not entirely clear, but it has been linked to the use of the appetite suppressant Fen-Phen. It also appears related to diseases such as liver disease and HIV infection. Doctors also believe the disease may have a genetic basis.
Bosentan works by blocking a naturally occurring protein called endothelin, a naturally occurring protein that occurs in higher levels in people with PPH and is harmful to the pulmonary arteries. The damaged, narrowed pulmonary arteries create the blood flow resistance that results in pulmonary hypertension. Bosentan, an orally-activated endothelin receptor antagonist, interferes with the protein and reverses its damaging effects, resulting in lower artery pressure.
"These findings offer great hope for patients who have this devastating disease," Dr. Channick said. The disease is more common in women between the ages of 21 and 40, however, it can affect anyone at any age. Symptoms of PPH include shortness of breath following exertion; excessive fatigue; dizziness, fainting and weakness; ankle swelling; bluish lips and skin, and chest pain.
This is the first-ever double-blind, placebo controlled study for PPH. The study evaluated 32 patients with pulmonary hypertension (primary or associated with scleroderma). Patients were randomly assigned to take either bosentan or a placebo. The patients given bosentan had improved exercise capacity, which worsened in patients on the placebo. Those on bosentan also experienced a decrease in blood pressure and improved heart function.
Until now, the only treatment for PPH has been intravenous Flolan, a form of the naturally occurring hormone prostacyclin. Flolan helps reduce damage in the blood vessel which lowers blood pressure. People with PPH respond to increased doses of prostacyclin, which dilates blood vessels in the lungs and throughout the body. Flolan is administered directly into the bloodstream through a surgically implanted catheter by a portable, battery-operated pump. Since the drug’s effects last only three to five minutes it must be constantly infused, slowly and continuously pumped into the body through the permanent catheter placed in a vein in the neck or chest.
Prior to the availability of Flolan, which was approved in 1995, there was no treatment for PPH. Patients would succumb to the disease within a few years after diagnosis, according to Channick.
"We have been searching for something that can work as well as Flolan, yet improve patients’ quality of life," Channick said. "The advantage of bosentan over Flolan is that it is non-invasive since it is an oral medication and only needs to be administered twice a day." Under the brand name Tracleer, developed by the drug company Actelion Ltd., bosentan has been deemed "approvable" by the U.S. Food and Drug Administration. The FDA plans to approve the drug pending finalization of the Tracleer label and the implementation of appropriate patient monitoring measure regarding liver enzymes and pregnancy prevention.
Joining UCSD in the study were University of Colorado Health Sciences Center; Baylor College of Medicine and the Methodist Hospital, Houston; Vanderbilt University School of Medicine; Hôpital Antoine Beclere, Clamart, France; and Duke University Medical Center.
The study was funded by Actelion Ltd.
Journal
The Lancet