Letairis (Ambrisentan)

Letairis (ambrisentan) is an approved therapy developed by Gilead Sciences to treat pulmonary arterial hypertension (PAH), or high blood pressure in the arteries of the lungs, a common complication of scleroderma.

Letairis, which can be used alone or in combination with Adcirca (tadalafil), improves  patients’ ability to exercise and prevents PAH from getting worse. However, it does not cure the disease.

How Letairis works

In scleroderma, the immune system mistakenly attacks healthy tissue, leading to damage that includes scarring. When this occurs in the blood vessels of the lungs, or pulmonary arteries, scar tissue can build up, narrowing the arteries. This results in blood vessels becoming smaller and stiffer, increasing the resistance to blood flow and pressure in the pulmonary arteries. Ultimately, less oxygen is supplied to the rest of the body, making it more difficult to exercise.

One response to an autoimmune attack is the body overproducing endothelin, a substance involved in controlling the contraction of artery wall muscle. When endothelin binds to an endothelin type-A receptor, it leads to arteries narrowing. On the other hand, if it binds to an endothelin type-B receptor, it leads to relaxing of muscles and widening of the arteries.

Letairis belongs to a class of medicines called endothelin receptor antagonists (ERA). It works by preventing endothelin from binding to endothelin type-A receptors. The result is pulmonary arteries relaxing, reducing blood pressure and allowing oxygen to be transported more effectively throughout the body.

Letairis in clinical trials

Results of the Phase 3 clinical trials ARIES-1 and ARIES-2 (NCT00091598) were key to regulatory approval of Letairis. The double-blind, randomized, placebo-controlled trials included 394 PAH patients. Participants were randomly assigned a high or low dose of Letairis, or a placebo, for 12 weeks.

The findings, published in the journal Circulation, demonstrated that the patients in the ARIES-1 trial who were taking Letairis saw a significant improvement in both their ability to exercise and their quality of life compared with those taking a placebo. In ARIES-2, the patients on Letairis saw an improvement, compared with the placebo group, but the difference was not statistically significant.

A two-year extension study, ARIES-E (NCT00578786), showed that Letairis was safe for long-term use. It also led to continued improvements in exercise ability and increased the time for the disease to worsen. The results appeared in the Journal of the American College of Cardiology.

The Phase 3b/4 AMBITION clinical trial (NCT01178073) assessed the effect of Letairis plus Adcirca compared with Letairis or Adcirca alone in people with PAH. The results on the first 500 patients completing the 18-month trial showed that using the two drugs in combination improved patients’ ability to walk, compared with each treatment alone. In addition, patients’ condition did not worsen and they were less likely to be hospitalized. The results were published in the New England Journal of Medicine.

The benefits of the Letairis-Adcirca combination therapy specifically in scleroderma-associated PAH was demonstrated in the open-label Phase 4 TPAHSS trial (NCT01042158). It involved 24 people with scleroderma-associated PAH who received the combination for 36 weeks at the Johns Hopkins University.

The trial compared changes in several patient measures after 36 weeks. The primary changes that researchers looked at were in right heart mass, measured by magnetic resonance imaging (MRI), and in resistance to blood flow in the lungs, measured by right heart catheterization.

After 36 weeks, there was a significant reduction in right heart mass, suggesting that the heart was under less strain, and blood flow through the lungs was significantly improved. The results appeared in the American Journal of Respiratory and Critical Care Medicine and the journal Pulmonary Circulation.

Additional information

The most common side effects of Letairis include swelling of the ankles and feet, headache, and fluid retention.

The drug was approved by the U.S. Food and Drug Administration (FDA) in 2007. The European Commission approved it in 2008. In Europe, Letairis is marketed by GlaxoSmithKline (GSK) under the brand name Volibris.

The Letairis-Adcirca combination therapy was approved by the FDA in October 2015, with European approval in November 2015. Adcirca is marketed by Eli Lilly in the U.S., with GSK holding the marketing rights in Europe.


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