People with pulmonary hypertension may soon have a new medication at their disposal, if the government gives the drug its endorsement. Encysive Pharmaceuticals, the manufacturer of the experimental oral medication, says it plans to seek approval from the Food and Drug Administration (FDA) to market sitaxsentan, also known by its marketing brand, Thelin®.
Improved Walking Distance Seen
The move to request approval of the drug hinged on the results of a Phase III trial (STRIDE-2) that evaluated the safety and effectiveness of the medication in people with pulmonary arterial hypertension (PAH). The randomized, double-blind, placebo-controlled trial lasted 18 weeks. It included a group of patients taking bosentan (Tracleer/Actelion), currently the only approved oral medication for pulmonary hypertension.
Patients were selected at random to receive one of two doses of sitaxsentan (50 or 100 milligrams), as well as placebo (all once per day), or bosentan twice per day. A total of 246 patients were recruited for the study in North America, Europe, Australia, and Israel.
The trial investigators found that the 100 mg dose of sitaxsentan improved walking distance in the PH patients taking the drug by nearly 31.5 meters (34.5 yards). The 50 mg dose improved walking distance by 24.2 meters (26.5 yards). Bosentan improved walking distance by 29 and-a-half meters (32.3 yards). All patients had taken part in a standard 6-minute walking test.
Measuring Patients' Functional Ability
Those patients taking placebo worsened in the test over the 18-week length of the trial, as investigators were anticipating. The researchers also found that each patient's physical function improved in the group taking the 100 mg dose of sitaxsentan. Each patient's function was measured based on a classification system developed by the World Health Organization:
• Class I: patients with no limitation of activities; they suffer no symptoms from ordinary activities.
• Class II: patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion.
• Class III: patients with marked limitation of activity; they are comfortable only at rest.
• Class IV: patients who should be at complete rest, confined to bed or chair; any physical activity brings on discomfort, and symptoms occur at rest.
How Safe Was the Drug?
Safety measurements were "encouraging", according to the study. Liver function abnormalities occurred in 3 percent of the patients given the 100 mg dose of the drug, compared to 5 percent of the patients taking the 50 mg dose, 11 percent taking bosentan, and 6 percent of those on placebo.
Four patients taking the 100 mg dose quit the trial for safety reasons or lack of effectiveness, compared to eight patients taking the 50 mg dose, nine patients in the bosentan group, and 11 of those taking placebo.
Of those patients, side effects were the reason two patients in the 100 mg group dropped out, as well as for four in the 50 mg group, six in the group taking bosentan and six patients in the placebo group. The most common side effects of sitaxsentan in the study were peripheral edema (100 mg), insomnia (50 mg), chest discomfort (50 mg), sinus congestion (100 mg), nausea (50 mg), pain in the upper abdomen (50 mg), and increased bleeding (100 mg).
The Next Step
"We will present more details from this trial at appropriate medical meetings over the next several months, and we are now focused on filing a New Drug Application (NDA) with the U.S. Food and Drug Administration in April 2005 to seek marketing authorization," said Bruce Given, MD, president and chief executive officer of Encysive Pharmaceuticals, the manufacturer of sitaxsentan. "This NDA submission will be closely followed by marketing applications in Europe and other territories."
Sitaxsentan works by blocking the action of endothelin, a compound that helps promote blood vessel narrowing. Endothelin is highly active in people with pulmonary hypertension.1 Thus, sitaxsentan falls into a class of drugs known as endothelin receptor antagonists. Bosentan, manufactured and marketed by Actelion Pharmaceuticals, is another drug in this class.
1. Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 2004 Feb 1;61(2):227-37.
John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.
