Pulmonary arterial hypertension - ambrisentan
Pulmonary arterial hypertension (PAH) is a serious condition, with no known cure. In sufferers, the blood pressure in the pulmonary artery, which supplies blood to the lungs, is continuously too high - about double the normal pressure of around 12 mmHg.
Pulmonary arterial hypertension (PAH) is a serious condition, with no known cure. In sufferers, the blood pressure in the pulmonary artery, which supplies blood to the lungs, is continuously too high - about double the normal pressure of around 12 mmHg.
This damages the endothelial cells that line the capillaries within the lung. The muscles in the arterial walls may tighten up as a result, narrowing the arteries, which means the heart has to work harder to pump blood through the lungs, and over time the heart muscle weakens, and can fail; heart failure is the most common cause of death in PAH patients. However, normal hypertension treatments do not work in primary pulmonary hypertension, and until the first prostacyclin-acting pulmonary vasodilators were developed, there was no treatment.
Another strategy is being investigated by Myogen, whose developmental drug ambrisentan is undergoing clinical trials. Endothelin ET-1 is overexpressed in various forms of pulmonary vascular disease, and oral endothelin receptor antagonists have been shown to improve pulmonary haemodynamics, exercise capacity and clinical outcome, with higher efficacy and lower incidences of adverse events than earlier treatments.1
Ambrisentan is a selective endothelin receptor A antagonist, and as well as showing promise in pulmonary hypertension, is also being investigated in chronic heart failure, hypertension and kidney failure. It has high bioavailability, and its half life is sufficiently long for once daily dosing.
A multicentre, double blind, dose finding clinical trial was carried out in 64 patients with moderate to severe PAH to evaluate the drug's safety, and its effect on exercise capacity. The patients were randomised to oral doses of 1, 2.5, 5 and 10 mg once a day for 12 weeks, followed by a 12 week open label dose adjustment period. Ambrisentan improved the six minute walking distance of the patients by over 30 metres, along with improvements in mean pulmonary artery pressure, pulmonary vascular resistance and cardiac index. All the doses were well tolerated throughout the entire trial2.
The FDA has given ambrisentan orphan drug status for pulmonary arterial hypertension, and two pivotal double blind, randomised, placebo controlled Phase III clinical trials are underway, one with doses of 2.5 and 5mg, and the second with doses of 5 and 10mg.