Endothelin-Receptor Antagonists
Overview
The launch of bosentan (Actelion’s Tracleer) in both the United States and Europe established a clear role for endothelin-receptor antagonists (ERAs) in the treatment of pulmonary arterial hypertension. However, bosentan inhibits both the endothelin-A (ET-A) and endothelin-B (ET-B) receptors, is associated with a high incidence of liver toxicity, and requires twice-daily dosing. These issues have prompted several pharmaceutical companies to pursue the development of novel agents in the ERA class. These novel agents are all selective for the ET-A-receptor subtype. In theory, ET-A-selective agents could block the vasoconstrictor effects of ET-A while maintaining the vasodilator and clearance effects of ET-B.
ET-A antagonists in the later stages of development include sitaxsentan (Encysive Pharmaceuticals’ Thelin) and Myogen’s ambrisentan. Other compounds in early development include Tanabe Seiyaku’s TA-0201 in Phase I, Abbott’s ABT-306552 in preclinical development, and two derivatives of sitaxsentan being developed by Encysive — namely, TBC-3711 in Phase I and TBC-3214 at the preclinical stage. The lack of published data precludes further discussion of these earlier-stage molecules.
Mechanism Of Action
Binding of ET-1 to its receptors activates signal trans-duction via the phospholipase C (PLC) intracellular signaling pathway, ultimately resulting in mitogenesis and vasoconstriction. ET-A receptors are expressed in vascular smooth muscle, the heart, the kidney, and the lung. ET-B receptors are also located on vascular smooth muscle, where activation elicits responses similar to those of ET-A receptors. However, ET-B receptors are also expressed in the endothelium, where activation leads to vasodilation through stimulation of the nitric oxide pathway. Small-molecule endothelin antagonists inhibit ET-1 action by binding endothelin receptors and inhibiting ligand (ET-1) interaction.
Sitaxsentan
Ambrisentan
Ambrisentan is an orally active ET-A selective antagonist being developed by Myogen under license from Abbott (formerly BASF Pharma) for the treatment of pulmonary arterial hypertension. The compound is also under investigation for cardiovascular disease and renal failure. Phase III trials for pulmonary arterial hypertension are under way. In July 2004,
the FDA awarded ambrisentan orphan drug status for pulmonary arterial hypertension and in March 2006 gave the product fast track status. Myogen has exclusive marketing rights to the compound. GSK has commercialization rights outside of the United States.
Inhibition of ET-A by ambrisentan counteracts the vasoconstrictive and mitogenic actions of endothelin in pulmonary arterial hypertension. Myogen reports the compound has a half-life of 9-15 hours and may therefore be suitable for once-daily dosing.
In May 2004, the results of a Phase II study of ambrisentan were presented at the American Thoracic Society conference in Orlando, Florida. Researchers randomized 64 patients (61% had primary pulmonary arterial hypertension [idiopathic or familial] and 39% had pulmonary arterial hypertension associated with scleroderma, human immunodeficiency virus, or anorexigen use) for a 12-week, blinded period to receive doses of 1, 2.5, 5, or 10 mg once daily A placebo arm was not included. The majority of the patients (64%) were NYHA functional class III, although some patients (36%) were class II. The initial blinded period was followed by a 12-week, open-label, dose-adjustment period. The study’s primary end point was a change in the 6MWD at week 12.
The study found that ambrisentan improved the 6MWD at all doses tested (1, 2.5, 5, and 10 mg daily) (33.9 m ± 9.6, [p = 0.003], 37 m ± 8.6 [p = 0.0004], 38.1m ± 13.2 [p = 0.011], and 35.1m ± 11.1, respectively) at week 12. At week 16, the mean increase in the 6MWD was 48.4 m for all groups. In patients with primary pulmonary arterial hypertension, a dose-dependent increase in the 6MWD was observed at week 12 ranging from 31.2 m to 54.1m. NYHA functional class improved by one in 31% of patients in the study and by two in 5.2% of patients. A worsening in functional class was experienced by 3.5% of patients. Improvements in Borg dyspnea index and hemodynamic parameters were also observed. Adverse events experienced were not dose-related. Four patients experienced elevations in liver transaminases three times above normal levels. One patient had to discontinue therapy, and one patient had to reduce the dose of the agent; the other two patients’ elevations were not confirmed on retesting. At the conclusion of the study, 48% of the patients were receiving the 10 mg/day dose of ambrisentan, and none experienced any liver abnormalities. No drug interactions were observed. This finding is extremely positive considering other ERAs appear to interact with warfarin. Myogen reports that 60-70% of the patients were receiving anticoagulant therapy.
Randomized, controlled Phase III studies for ambrisentan, which include a placebo arm, are under way. The Ambrisentan in Patients with Moderate-to-Severe Pulmonary Arterial Hypertension (ARIES) I trial is investigating 5 and 10 mg/day doses of ambrisentan for 12 weeks in the United States and Canada, while ARIES II is evaluating the 2.5 and 5 mg/day doses over 12 weeks in Europe and South America. The primary efficacy end point is improvement in the 6MWD. The company completed these trials in August 2005.
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