16 Cardiovascular Medicine FAMILY P RACTICE N EWS • August 15, 2005 Sitaxsentan Proves Sitaxsentan Better Tolerated Than Effective in Pulmonary Bosentan as Oral PAH Therapy

BY BRUCE GOLDMAN (the “safety subset”), 1 because of a rash, and Arterial Hypertension Contributing Writer 12 because of liver toxicity (liver enzyme el- evations to greater than three times the up- The phase III trial found that the 100-mg dose S AN D IEGO — The investigational drug per limit of normal). Liver toxicity histori- sitaxsentan was safe and effective for treating cally occurs in 10%-15% of patients treated improved WHO functional class vs. placebo. pulmonary arterial hypertension in a study with bosentan. of 48 patients for whom the only currently Patients in each of the two subsets were BY BRUCE GOLDMAN er might be desirable. Bosentan blocks approved oral therapy, bosentan, was inef- randomized to 50 mg or 100 mg of sitaxsen- Contributing Writer both receptor types, while sitaxsentan fective or toxic. tan and tested 12 weeks later for changes in is extremely selective for ET-A, Dr. The findings suggest that “patients who 6-minute walk distance, WHO functional S AN D IEGO — An investigational Barst said. are getting a good therapeutic benefit from class (an index of severity), and Borg dysp- drug, sitaxsentan, improved exercise ca- Moreover, bosentan has been asso- an endothelin antagonist, but are having nea score (a measure of breathing difficulty). pacity and World Health Organization ciated with relatively high rates of liv- problems with liver toxicity on bosentan, can At the trial’s end, 5 of the 15 subjects on functional class in patients with pul- er function abnormalities. Sitaxsentan be safely changed to sitaxsentan with a low the 100-mg sitaxsentan dose in the efficacy monary arterial hypertension in a phase has oral bioavailability exceeding 90% likelihood of recurrence, and thereby still get subset showed at least 15% improvements in III trial, Robyn J. Barst, M.D., reported and a relatively long duration of ac- the benefit of an endothelin antagonist,” 6-minute walk distance, with similar results at the 100th International Conference of tion, permitting dosing on a once-a- Raymond Benza, M.D., said at the 100th In- for the other two efficacy criteria. (The 50- the American Thoracic Society. day basis, she said. ternational Conference of the American mg dose had lower efficacy.) In total, five pa- The drug also exhibited a favorable In the 6-minute walk, the primary Thoracic Society. tients in the efficacy subset dropped out of safety profile. end point in STRIDE-2, the sitaxsentan Both bosentan and sitaxsentan are orally the study before its completion. None of the STRIDE-2 (Sitaxsentan to Relieve 100-mg group had a statistically sig- administered endothelin-receptor antago- 35 patients in this subset experienced any liv- Impaired Exercise) was a 246-patient, nificant increase of 31.4 meters over nists, but bosentan blocks both the “A” and er toxicity on sitaxsentan. 18-week, randomized, double- “B” receptor subtypes, whereas sitaxsentan All 13 patients in the safety subset (4 on 50 blind, placebo-controlled clinical At 100 mg, is highly selective for the A subtype. Unlike mg and 9 on 100 mg of sitaxsentan) com- trial of sitaxsentan, which is in de- sitaxsentan twice-daily bosentan, sitaxsentan can be giv- pleted the study, and 12 had no recurrence velopment by Encysive Pharma- ‘is safe and en once daily because it is metabolized dif- of their toxicity after being placed on ceuticals under the trade name efficacious, with a ferently and has a longer duration of action, sitaxsentan. None showed significant dete- Thelin. low incidence of said Dr. Benza of the University of Alabama, rioration in their clinical condition. A single “STRIDE-2 confirmed what its acute Birmingham. patient, who had developed liver toxicity af- predecessor, STRIDE-1, showed: hepatotoxicity.’ All patients in the randomized, double- ter 1 month on bosentan and again on Sitaxsentan at 100 mg is safe and blind, multicenter trial, called STRIDE-6, ei- bosentan rechallenge after a 4-week inter- efficacious, with a low incidence DR. BARST ther had idiopathic (primary) pulmonary ar- ruption, experienced elevated liver enzymes of acute hepatotoxicity,” said Dr. terial hypertension (PAH) or had developed during week 12 of therapy with 100 mg of Barst, professor of pediatrics at Co- placebo, with open-label bosentan in- the syndrome as a consequence of having ei- sitaxsentan. The liver enzyme elevation sub- lumbia University, New York, and di- creasing the distance by 29.5 meters ther connective tissue disease or congenital sided after sitaxsentan therapy was stopped. rector of New York Presbyterian Hos- over placebo. Among patients on the heart disease. Encysive Pharmaceuticals has since filed pital’s Pulmonary Hypertension 100-mg sitaxsentan dose, the 6-minute Overall, 35 of the patients in the study had a New Drug Application with the Food Center. walk distance appeared on average to discontinued bosentan because of an inade- and Drug Administration for approval of In the study, conducted at 55 cen- continue improving after week 12; quate clinical response (the “efficacy sub- the 100-mg dose of sitaxsentan, under the ters around the world, about 60 pa- bosentan’s efficacy appeared to peak at set”). The other 13 patients had discontinued trade name Thelin, as a first-line oral ther- tients were randomized to once-dai- week 12 and then trend downward. bosentan therapy because of safety issues apy for PAH. ■ ly oral doses of 50 mg or 100 mg of Sitaxsentan at 100 mg, but not open- sitaxsentan or placebo. An additional label bosentan, improved World 60 patients received twice-daily, open- Health Organization functional class label doses of bosentan (Tracleer, versus placebo. Sitaxsentan at 100 mg, First Inhaled Drug for PAH Approved marketed by Actelion Pharmaceuti- but not at 50 mg, trended toward clin- cals), the only currently approved oral ical significance in delaying clinical he Food and Drug administration ap- ment in at least one New York Heart Asso- medication for pulmonary arterial hy- worsening, Dr. Barst reported. Tproved the first inhaled therapy for pul- ciation PAH class, and no death or deterio- pertension (PAH). At 18 weeks, the 100-mg sitaxsentan monary arterial hypertension. ration. Adverse responses with iloprost in- PAH is uncommon, affecting an es- dose was associated with a 3% rate of Iloprost, a stable synthetic analogue of cluded flushing, cough, jaw pain, and timated 100,000-200,000 people world- liver function abnormality (liver en- prostacyclin, causes selective pulmonary va- headache. wide, but the prevalence is rising with zyme elevations to greater than three sodilation, improving exercise capacity and Iloprost is dispensed in single-use glass am- the advent of noninvasive diagnostic times the upper limit of normal), com- hemodynamics in patients with PAH. pules (2 mL) containing 20 mcg iloprost for methods and improved treatment. Re- pared with 6% for placebo and 11% for The drug is a strong vasodilator and in- inhalation via the Prodose Adaptive Aerosol lentlessly progressive, the disease is bosentan. Liver enzyme abnormali- hibitor of platelet aggregation. The inhala- Delivery system. Labeling indicated that ilo- characterized by high blood pressure ties reversed in all cases. These results tion formulation (Ventavis Inhalant Solu- prost should not be inhaled more than once and extensive remodeling of pul- are consistent with earlier studies of tion) was developed to replace continuous every 2 hours, and the drug is not effective monary arterial walls. Without lung or the two drugs and with bosentan’s infusion prostacyclin, which was the first while a patient is sleeping. Vital signs should heart/lung transplantation, PAH is in- package insert. Other adverse effects of therapy shown to reduce mortality in a con- be monitored when initiating iloprost be- evitably fatal, with a median survival sitaxsentan didn’t appear to have high trolled study of patients with severe pul- cause of the risk of syncope. of about 2.8 years. clinical significance, she said. monary hypertension. In nature, prostacy- Iloprost, though not yet commercially One of the hallmarks of PAH is a About 72% of STRIDE-2 subjects clin is a local hormone; intravenous available in the United States, will be mar- high level of endothelin in the pul- were on warfarin, a blood-thinning introduction can result in systemic side ef- keted by CoTherix Inc. as the Ventavis In- monary vasculature. Endothelin is a agent commonly prescribed for PAH fects and progressive tolerance, requiring halant Solution under exclusive contract potent mediator of both blood-vessel patients. Sitaxsentan inhibits, and more and more of the drug. with Schering AG, which markets the drug constriction and smooth-muscle pro- bosentan enhances, the metabolism The randomized clinical trial reported for in Europe and Australia. liferation. Two endothelin receptor of warfarin, the levels of which must approval was conducted on 203 adult pa- CoTherix had previously received orphan subtypes, designated ET-A and ET-B, therefore be monitored and in many tients with PAH; 101 received inhaled ilo- drug designation for iloprost from the FDA, reside on pulmonary endothelial and cases decreased when sitaxsentan is prost, and 102 received placebo. The re- in August 2004. smooth-muscle cells. coadministered. sponse rate in the iloprost group (6-9 Iloprost is also undergoing continuing Animal and human studies have sug- In this trial, bosentan necessitated inhalations per day) was 19%, compared clinical trials in the United States to examine gested that, whereas ET-A is strongly about the same number of per-patient with 4% for the placebo group. The re- its interaction with other drug treatments for implicated in the etiology of PAH, warfarin dose adjustments as did sponse rate was determined using a prima- PAH, as well as for its potential as a preven- ET-B’s role may be beneficial, and sitaxsentan, but in the opposite direc- ry composite end point that incorporated tive agent for lung cancer in heavy smokers. therefore that a selective ET-A block- tion, Dr. Barst reported. ■ improvement in exercise capacity, improve- —Mark S. Lesney