SAN DIEGO — An investigational drug, sitaxsentan, improved exercise capacity and World Health Organization functional class in patients with pulmonary arterial hypertension in a phase III trial, Robyn J. Barst, M.D., reported at the 100th International Conference of the American Thoracic Society.
The drug also exhibited a favorable safety profile.
STRIDE-2 (Sitaxsentan to Relieve Impaired Exercise) was a 246-patient, 18-week, randomized, double-blind, placebo-controlled clinical trial of sitaxsentan, which is in development by Encysive Pharmaceuticals under the trade name Thelin.
“STRIDE-2 confirmed what its predecessor, STRIDE-1, showed: Sitaxsentan at 100 mg is safe and efficacious, with a low incidence of acute hepatotoxicity,” said Dr. Barst, professor of pediatrics at Columbia University, New York, and director of New York Presbyterian Hospital's Pulmonary Hypertension Center.
In the study, conducted at 55 centers around the world, about 60 patients were randomized to once-daily oral doses of 50 mg or 100 mg of sitaxsentan or placebo. An additional 60 patients received twice-daily, open-label doses of bosentan (Tracleer, marketed by Actelion Pharmaceuticals), the only currently approved oral medication for pulmonary arterial hypertension (PAH).
PAH is uncommon, affecting an estimated 100,000–200,000 people worldwide, but the prevalence is rising with the advent of noninvasive diagnostic methods and improved treatment. Relentlessly progressive, the disease is characterized by high blood pressure and extensive remodeling of pulmonary arterial walls. Without lung or heart/lung transplantation, PAH is inevitably fatal, with a median survival of about 2.8 years.
One of the hallmarks of PAH is a high level of endothelin in the pulmonary vasculature. Endothelin is a potent mediator of both blood-vessel constriction and smooth-muscle proliferation. Two endothelin receptor subtypes, designated ET-A and ET-B, reside on pulmonary endothelial and smooth-muscle cells.
Animal and human studies have suggested that, whereas ET-A is strongly implicated in the etiology of PAH, ET-B's role may be beneficial, and therefore that a selective ET-A blocker might be desirable. Bosentan blocks both receptor types, while sitaxsentan is extremely selective for ET-A, Dr. Barst said.
Moreover, bosentan has been associated with relatively high rates of liver function abnormalities. Sitaxsentan has oral bioavailability exceeding 90% and a relatively long duration of action, permitting dosing on a once-a-day basis, she said.
In the 6-minute walk, the primary end point in STRIDE-2, the sitaxsentan 100-mg group had a statistically significant increase of 31.4 meters over placebo, with open-label bosentan increasing the distance by 29.5 meters over placebo. Among patients on the 100-mg sitaxsentan dose, the 6-minute walk distance appeared on average to continue improving after week 12; bosentan's efficacy appeared to peak at week 12 and then trend downward.
Sitaxsentan at 100 mg, but not open-label bosentan, improved World Health Organization functional class versus placebo. Sitaxsentan at 100 mg, but not at 50 mg, trended toward clinical significance in delaying clinical worsening, Dr. Barst reported.
At 18 weeks, the 100-mg sitaxsentan dose was associated with a 3% rate of liver function abnormality (liver enzyme elevations to greater than three times the upper limit of normal), compared with 6% for placebo and 11% for bosentan. Liver enzyme abnormalities reversed in all cases. These results are consistent with earlier studies of the two drugs and with bosentan's package insert. Other adverse effects of sitaxsentan didn't appear to have high clinical significance, she said.
About 72% of STRIDE-2 subjects were on warfarin, a blood-thinning agent commonly prescribed for PAH patients. Sitaxsentan inhibits, and bosentan enhances, the metabolism of warfarin, the levels of which must therefore be monitored and in many cases decreased when sitaxsentan is coadministered.
In this trial, bosentan necessitated about the same number of per-patient warfarin dose adjustments as did sitaxsentan, but in the opposite direction, Dr. Barst reported.