Sitaxsentan
Sitaxsentan (Thelin) is an orally active ET-A-selective ERA being developed by Encysive Pharmaceuticals (formerly Texas Biotechnology) for the treatment of cardiovascular diseases, including pulmonary arterial hypertension and chronic congestive heart failure (CHF). The FDA granted sitaxsentan orphan drug designation for the treatment of pulmonary arterial hypertension in November 2004, an action that ensures seven years of marketing exclusivity for pulmonary arterial hypertension and confers tax and procedural advantages. Phase III studies for pulmonary arterial hypertension are under way.
Sitaxsentan is 6,500-fold more selective for the ET-A receptor than the ET-B receptor. Selective inhibition of ET-A counteracts the vasoconstrictive and mitogenic actions of endothelin in pulmonary arterial hypertension. Animal investigations showed the agent had a half-life of six to seven hours and good oral bioavailability. Human studies determined a similar pharmacokinetic profile (half-life of five to seven hours).
Clinical studies assessing the actions of sitaxsentan in pulmonary arterial hypertension are available. The Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) study, a randomized, double-blind, placebo-controlled Phase Ilb/IIII trial, examined the effects of two doses of sitaxsentan (100 mg and 300 mg) administered orally, once daily to 178 pulmonary arterial hypertension patients. The study lasted 12 weeks. Patients were NYHA functional class II, III, or IV and had pulmonary arterial hypertension, pulmonary arterial hypertension associated with connective tissue disease, or pulmonary arterial hypertension associated with congenital pulmonary shunts. The primary end point of maximum oxygen consumption was not reached, but those in the drug-treated arm did show improvements in the 6MWD and NHYA functional class. Sitaxsentan-treated patients experienced an improvement in the 6MWD of 35 m (p < 0.01) for those receiving the 100 mg dose and 33 m (p < 0.01) for those receiving 300 mg. NYHA functional class improved in 29% (16 out of 55) of the 100 mg group and in 30% (19 out of 63) of the 300 mg group. In the placebo group, 15% (9 out of 60) of patients demonstrated an improvement in NYHA functional class. Hemodynamic improvements were also observed on treatment with sitaxsentan.
A post hoc analysis of data from the STRIDE-1 study presented at the November 2004 meeting of the American Heart Association (AHA) in New Orleans revealed that sitaxsentan improved the 6MWD, NYHA functional class, and hemodynamics in pulmonary arterial hypertension patients with connective tissue disease.
A blinded, follow-up study examined the effects of chronic sitaxsentan in patients who had taken part in STRIDE-1. Seventy-nine patients received the 100 mg dose while 91 received 300 mg. The median length of treatment was 26 weeks, although some patients received therapy for up to 59 weeks. The study’s end point was the effect of sitaxsentan on NYHA functional class. The researchers also analyzed the time to first improvement and the rate at which patients deteriorated. Results demonstrated that 53% of the patients in the 100 mg group had an improvement of one NYHA functional class, while 44% in the 300 mg group showed a similar improvement. During the study, 5% of patients in the 100 mg group and 8% in the 300 mg group deteriorated.
Based on data collected from bosentan studies, liver enzyme abnormalities are of prime concern when treating patients with ERAs, and indeed, elevated liver transaminases appear to be a problem with sitaxsentan. In the STRIDE-1 study, 10% of patients receiving 300 mg sitaxsentan experienced liver function abnormalities. In the follow-up study, no liver enzyme abnormalities (three times above normal levels) were reported in the first 12 weeks of the investigation, although over the entire course of therapy, overall rates were 5% for the 100 mg dose and 21% for the 300 mg dose. It should also be noted that in a pilot study of sitaxsentan, higher doses were associated with fatal hepatitis.
Other commonly experienced adverse events reported in STRIDE-1 were headache, peripheral edema, nausea, and nasal congestion. These effects have been reported with other ERAs. Treatment with sitaxsentan also appears to increase the international normalized ratio (INR) in patients treated with warfarin. Interactions with warfarin are due to sitaxsentan’s inhibition of the CYP2 C9 P450 enzyme, which is the principal hepatic enzyme involved in warfarin metabolism.
Further Phase III trials for sitaxsentan are under way. In September 2004, Encysive announced it had completed enrolling 240 pulmonary arterial hypertension patients in the company’s multicenter pivotal study, STRIDE-2. STRIDE-2 is a randomized, double-blind, placebo-controlled study of sitaxsentan with a blinded bosentan arm. Patients will be randomized to receive one of four treatments: 50 mg sitaxsentan once daily, 100 mg sitaxsentan once daily, placebo once daily, or bosentan twice daily according to the package insert. STRIDE-2 will last 18 weeks. Data from STRIDE-2 were announced in February 2005, and the NDA officially filed in May 2005.
Following data from STRIDE-4 (a small trial designed to test whether the 50 mg dose was equivalent to the 100 mg dose) presented at an Encysive Pharmaceuticals press conference, the company is not hopeful about the results for the 50 mg dose in STRIDE-2. In STRIDE-4, the 50 mg dose demonstrated no meaningful efficacy trends on any of the parameters tested.
The company also recently reported data from a small study of 24 healthy volunteers conducted to examine potential drug interactions between sitaxsentan and sildenafil. Results demonstrated that the addition of sildenafil to a sitaxsentan treatment regimen did not appear to alter sitaxsentan levels. In the presence of sitaxsentan, the maximum concentration (Cmax) of sildenafil increased by 18%. The minor effects on sildenafil pharmacokinetics are thought to be due to weak cytochrome P450 inhibition seen in earlier studies in cultured hepatocyte studies. Nevertheless, Encysive does not expect an adjustment to sildenafil’s label will be required.
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