Letairis (ambrisentan) is approved to treat the symptoms of pulmonary arterial hypertension (PAH). It is marketed by Gilead in the U.S., and by GlaxoSmithKline (GSK) in Europe, under the brand name Volibris.

The treatment is approved to treat patients with WHO functional class 2 or 3 PAH (WHO group 1) both as a monotherapy and in combination with Adcirca (tadalafil) in the U.S. and Europe.

How Letairis works

PAH is associated with a severe narrowing of the blood vessels in the lungs (the pulmonary arteries). This narrowing leads to elevated blood pressure, as the blood cannot flow as easily, and to a poorer transport of oxygen throughout the body, making exercise more difficult for patients. One cause of this narrowing is the contraction of the muscles of the arterial walls.

The active component of Letairis, ambrisentan, is an endothelin type-A receptor antagonist. The endothelin type-A receptor, when activated by its ligand endothelin-1, signals for vascular smooth muscles to contract, a process also known as vasoconstriction. Endothelin-1 can also activate endothelin type-B receptors, which are associated with vasodilation, or the relaxation of the muscles and the widening of the arteries.

Letairis competes with endothelin by blocking its binding sites on endothelin type-A receptors. Letairis is selective for the type-A receptors, allowing endothelin-1 to continue binding to type-B receptors. When less endothelin is able to bind to the type-A receptor, it’s less active. This, in turn, reduces vascular smooth muscle contraction, resulting in vasodilation. Ultimately, there is less resistance to blood flowing through the arteries of the lungs, so blood pressure is lower and oxygen can be transported more effectively around the body.

Letairis in clinical trials

Letairis was initially approved based on the results of two randomized, double-blind, placebo-controlled Phase 3 clinical trials, called ARIES-1 and ARIES-2 (NCT00091598). ARIES-1 took place in North America, and ARIES-2 in Europe, South America, and Israel. In total, 394 patients were enrolled to receive either a high or low dose of Letairis, or a placebo, for 12 weeks.

Results were published in the scientific journal Circulation. The treatment’s efficacy was measured by the change (from study’s start) in the distance that patients could walk in six minutes. Those taking Letairis saw a significant improvement in walking distance, while patients taking placebo saw an overall decline. Other measures of efficacy, including time until the disease worsened and quality of life, were significantly improved in the Letairis group in ARIES-2. Patients on Letairis in ARIES-1 also improved compared to the placebo, but the difference was not significant.

This was followed by an extension study, ARIES-E (NCT00578786), to investigate the long-term safety and efficacy of Letairis over a two-year period. The results, published in the Journal of the American College of Cardiology, suggested that Letairis was safe for extended use, and associated with continued improvements in exercise ability and a reduced risk of the disease worsening.

The Letairis/Adcirca combination therapy was approved as a PAH treatment based on a Phase 3b/4 trial (NCT01178073) called AMBITION. This trial compared the effects of three different treatment regimens: Letairis with Adcirca, Letairis with a placebo, and Adcirca with a placebo.

In total, 610 PAH  patients were randomized to one of the treatment groups as a first-line therapy (i.e., before taking other medication). The initial results from the first 500 patients, published in the New England Journal of Medicine, suggested that the combination therapy was associated with a significantly better clinical response and an improvement in exercise ability after 24 weeks. For example, those taking the combination  had a median improvement of 49 metres in the distance walked in six minutes, compared to an improvement of 24 meters in the pooled monotherapy groups.  

The combination therapy was associated with a reduced chance of the disease worsening, with 11 percent of patients worsening after one year, compared to 24 percent of those on monotherapy.

Other information

The most common side effects associated with this treatment include swelling of the ankles and feet, headache, and fluid retention.

In June 2007, the U.S. Food and Drug Administration (FDA) granted Gilead approval to market Letairis as a PAH therapy. The European Commission approved the therapy, under the name Volibris, in April 2008.

The FDA approved the Letairis and Adcirca combination therapy in October 2015, closely followed by the European Commission in November 2015. Adcirca is marketed by Eli Lilly, while GSK holds the marketing rights in Europe.


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