Myogen, Inc., a biopharmaceutical company focused on the discovery, development and commercialization of small molecule therapeutics for the treatment of cardiovascular disorders, has initiated a clinical trial to evaluate ambrisentan in patients with pulmonary arterial hypertension (PAH) who have previously discontinued bosentan or sitaxsentan therapy due to liver function test (LFT) abnormalities, specifically elevated serum aminotransferase concentrations.
The primary objective of this trial is to determine the incidence of increased serum aminotransferase concentrations associated with ambrisentan therapy in patients who have previously discontinued bosentan or sitaxsentan therapy due to serum aminotransferase abnormalities. This trial will also evaluate the overall safety, tolerability and efficacy of ambrisentan in this patient population.
Previous clinical trials with bosentan (BREATHE-1) and sitaxsentan (STRIDE-1) have demonstrated dose-dependent increases in serum aminotransferase concentrations, specifically alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) concentrations, requiring withdrawal of therapy for reasons of safety. Preclinical studies suggest that serum aminotransferase elevations induced by bosentan and chemically-related compounds may be due to their direct competition with bile salts for active transport across the hepatocyte membrane into the bile canaliculi.
Ambrisentan is an ETA selective endothelin receptor antagonist being developed as an oral therapy for patients with PAH. Ambrisentan has been granted orphan drug designation for the treatment of PAH in both the United States and European Union. The Company completed a Phase 2 clinical trial of ambrisentan in September 2003.