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Sitaxsentan Phase III Study Improves Walking Distance in Patients With Pulmonary Arterial Hypertension

HOUSTON, Feb. 17 /PRNewswire-FirstCall/ -- Encysive Pharmaceuticals (NASDAQ:ENCY) today announced the publication of an article titled "Sitaxsentan Therapy for Pulmonary Arterial Hypertension" in the February 15 issue of the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine (AJRCCM) (Vol. 169, pp. 441-447). The full article can be found on American Thoracic Society's website at .

The reported study is based on Encysive's Phase IIb/III STRIDE-1 (Sitaxsentan To Relieve ImpaireD Exercise) clinical study in Pulmonary Arterial Hypertension (PAH). The author and lead investigator of the study, Robyn J. Barst, M.D., Director, New York Presbyterian Pulmonary Hypertension Center, Columbia University College of Physicians and Surgeons, New York, NY, concluded that sitaxsentan at doses of 100 mg or 300 mg administered orally once daily improved six-minute walk distance by 35 and 33 meters, respectively, after 12 weeks of treatment in PAH patients. In addition, New York Heart Association (NYHA) functional class, cardiac output and pulmonary vascular resistance also improved.

The 178 patient STRIDE-1 trial included a broader range of patients than previously studied in the comparable multi-center trial with the marketed, non-selective endothelin receptor antagonist bosentan. Sitaxsentan is a selective endothelin A receptor antagonist.

"While each of the patient groups appeared to have benefited from sitaxsentan treatment, when data on the STRIDE-1 patients who would have qualified for inclusion in the bosentan BREATHE-1 trial were analyzed, the treatment effect for sitaxsentan increased to 65 meters in the six-minute walk test," reported Dr. Barst. "This compares to the reported 44 meter treatment effect for bosentan in the 213-patient pivotal BREATHE-1 study. The ongoing pivotal study, STRIDE-2, evaluates both endothelin receptor antagonists."

"This study published in the AJRCCM supports our strategy in developing sitaxsentan," commented Bruce D. Given, M.D., President and CEO of Encysive. "Our second pivotal study, STRIDE-2, is currently enrolling patients with Class II-IV pulmonary arterial hypertension in North America and Europe. We believe results from this study, combined with results from other trials, will further define the ability of sitaxsentan to successfully treat a broad range of patients diagnosed with PAH."

About STRIDE-1 and STRIDE-2
The STRIDE-1 trial was a randomized, double-blind, placebo-controlled, 12-week study in 178 patients. Included were patients with NYHA Class II-IV primary pulmonary hypertension, PAH related to connective tissue disease or PAH related to congenital heart disease; there was no upper limit to baseline walk for inclusion in the study, i.e. patients with baseline six-minute walk >450 meters were not excluded. Patients received either sitaxsentan 100 mg, sitaxsentan 300 mg or placebo treatment once a day and were treated for 12 weeks. Sitaxsentan 100 mg and 300 mg provided similar improvements in exercise capacity (six-minute walk), functional class and hemodynamics.

Of the 178 patients enrolled in STRIDE-1, none of the patients in the 100 mg group discontinued due to adverse events or for other reasons, versus five patients from the placebo group and seven from the 300 mg group. The most frequent adverse events that occurred in patients receiving sitaxsentan and that were more common than in placebo-treated patients were headache, peripheral edema, nausea, nasal congestion and dizziness. Liver abnormalities have previously been recognized as complications related to the endothelin antagonist class of drugs. Liver abnormalities in the STRIDE-1 trial were defined as elevated serum aminotransferase values that were more than three times normal. Incidences of liver abnormalities in STRIDE-1, which reversed in all cases, were 3% for the placebo group, 0% for the sitaxsentan 100 mg group and 9.5% for the sitaxsentan 300 mg group. When experiences from STRIDE-1 and its extension trial, resulting in total patient exposures of as long as 58 weeks are considered, 5% of patients receiving 100 mg and 21% receiving 300 mg of sitaxsentan developed elevations. All elevations resolved with discontinuation of study drug.

Given the similarity in efficacy between the 100 mg and 300 mg dose groups and the improved safety profile of the 100 mg dose, 100 mg once daily has been selected as the maximum dose in the ongoing clinical program.

STRIDE-2 is a 240 patient trial including patients with WHO (NYHA modified for PAH) Class II-IV PAH of primary or secondary etiologies (due to collagen vascular disease or certain congenital heart defects) with an entry six-minute walk distance of less than or equal to 450 meters. Patients are being randomized to receive placebo, 50 or 100 mg of sitaxsentan or bosentan. The STRIDE-2 program is being conducted under a Special Protocol Assessment with the U.S. Food and Drug Administration.

About Sitaxsentan and PAH
Sitaxsentan is a small molecule that antagonizes the action of endothelin, a potent mediator of blood vessel constriction and growth of smooth muscle in vascular walls. Endothelin receptor antagonists may prove to be effective in the treatment of a variety of diseases where the regulation of vascular constriction is important. Sitaxsentan is a highly selective endothelin A receptor antagonist and is 6500 times more selective for endothelin A than endothelin B receptors.

Pulmonary arterial hypertension is a condition that involves high blood pressure and structural changes in the walls of the pulmonary arteries, which are the blood vessels that connect the right side of the heart to the lungs. PAH causes shortness of breath, limits activity and shortens life-expectancy. PAH is estimated to afflict around 100,000 people worldwide, many of whom are young adults.

Source: Encysive Pharmaceuticals

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