SAN DIEGO — The investigational drug sitaxsentan was safe and effective for treating pulmonary arterial hypertension in a study of 48 patients for whom the only currently approved oral therapy, bosentan, was ineffective or toxic.
The findings suggest that “patients who are getting a good therapeutic benefit from an endothelin antagonist, but are having problems with liver toxicity on bosentan, can be safely changed to sitaxsentan with a low likelihood of recurrence, and thereby still get the benefit of an endothelin antagonist,” Raymond Benza, M.D., said at the 100th International Conference of the American Thoracic Society.
Both bosentan and sitaxsentan are orally administered endothelin-receptor antagonists, but bosentan blocks both the “A” and “B” receptor subtypes, whereas sitaxsentan is highly selective for the A subtype. Unlike twice-daily bosentan, sitaxsentan can be given once daily because it is metabolized differently and has a longer duration of action, said Dr. Benza of the University of Alabama, Birmingham.
All patients in the randomized, double-blind, multicenter trial, called STRIDE-6, either had idiopathic (primary) pulmonary arterial hypertension (PAH) or had developed the syndrome as a consequence of having either connective tissue disease or congenital heart disease.
Overall, 35 of the patients in the study had discontinued bosentan because of an inadequate clinical response (the “efficacy subset”). The other 13 patients had discontinued bosentan therapy because of safety issues (the “safety subset”), 1 because of a rash, and 12 because of liver toxicity (liver enzyme elevations to greater than three times the upper limit of normal). Liver toxicity historically occurs in 10%–15% of patients treated with bosentan.
Patients in each of the two subsets were randomized to 50 mg or 100 mg of sitaxsentan and tested 12 weeks later for changes in 6-minute walk distance, WHO functional class (an index of severity), and Borg dyspnea score (a measure of breathing difficulty).
At the trial's end, 5 of the 15 subjects on the 100-mg sitaxsentan dose in the efficacy subset showed at least 15% improvements in 6-minute walk distance, with similar results for the other two efficacy criteria. (The 50-mg dose had lower efficacy.) In total, five patients in the efficacy subset dropped out of the study before its completion. None of the 35 patients in this subset experienced any liver toxicity on sitaxsentan.
All 13 patients in the safety subset (4 on 50 mg and 9 on 100 mg of sitaxsentan) completed the study, and 12 had no recurrence of their toxicity after being placed on sitaxsentan. None showed significant deterioration in their clinical condition. A single patient, who had developed liver toxicity after 1 month on bosentan and again on bosentan rechallenge after a 4-week interruption, experienced elevated liver enzymes during week 12 of therapy with 100 mg of sitaxsentan. The liver enzyme elevation subsided after sitaxsentan therapy was stopped.
Encysive Pharmaceuticals has since filed a New Drug Application with the Food and Drug Administration for approval of the 100-mg dose of sitaxsentan, under the trade name Thelin, as a first-line oral therapy for PAH.