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Title: Fewer Liver Function Abnormalities Seen With Sitaxsetan in Pulmonary Hypertension: Presented at CHEST

"Fewer Liver Function Abnormalities Seen With Sitaxsetan in Pulmonary Hypertension: Presented at CHEST"

By Ed Susman MONTREAL, CANADA -- November 2, 2005 -- Significantly fewer patients with pulmonary arterial hypertension experienced abnormal liver function tests while on the investigational endothelin receptor antagonist sitaxsetan than while on bosentan, researchers reported here at the American College of Chest Physicians Annual Meeting (CHEST). "Long-term treatment with sitaxsetan 100 mg once daily results in significantly fewer liver function abnormalities than [with] bosentan," said Terrence Coyne, MD, chief medical officer, Encysive Pharmaceuticals, Houston, Texas, United States, which is developing sitaxsetan and funded the study. Dr. Coyne reported on the extension study of sitaxsetan, in which 145 patients on sitaxsetan 100-mg dose were compared with 84 patients on the open-label efficacy-rated dose of bosentan. About 4.4% of patients on sitaxsetan experienced abnormal liver enzyme tests, defined as 3 times that of the upper limit of normal, compared with 14.8% of patients on bosentan (P = .014), Dr. Coyne said in an oral presentation November 1[^st.

Bosentan is a dual nonselective antagonist of the endothelin receptors ETa and ETb. Sitaxsetan is a highly selective antagonist of ETa, Dr. Coyne said.

"Bosentan therapy has been complicated by abnormal liver function tests in a controlled trial setting and in clinical practice, a finding that has been subsequently seen at varying rates with all endothelin receptor antagonists studied in pulmonary arterial hypertension," he said.

The results seen in the sitaxsetan extension trial, performed as part of its application for approval with the US Food and Drug Administration, appear to be consistent with previous studies, in which both 50-mg and 100-mg levels of sitaxsetan were tested among patients with pulmonary arterial hypertension.

In the first 18-week study, about 4% of patients on sitaxsetan experienced abnormal liver function tests compared with 18.7% of those on bosentan, Dr. Coyne said. That difference reached statistical significance at the P = .009 level.

Richard Chinnock, MD, assistant professor of medicine, University of California at San Diego, La Jolla, California, United States, suggested that because patients were switched from 50 mg to 100 mg in the extension study, the sitaxsetan arm benefited from having fewer adverse effects due to a less potent sitaxsetan dosing.

However, Dr. Coyne noted that abnormal liver tests occurred in placebo patients and were at even a higher rate with the 50-mg dose of sitaxsetan. He suggested that higher, more efficacious doses of sitaxsetan were showing therapeutic gains by decreasing stress on the liver.

[Presentation title: Sitaxsentan Therapy in Pulmonary Arterial Hypertension Results in Significantly Fewer Liver Function Abnormalities Than Bosentan.]

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