At least one shortcoming of currently available therapy for pulmonary arterial hypertension may become irrelevant with the Food and Drug Administration approval of the endothelin receptor antagonist ambrisentan last month.
In a statement issued by the FDA announcing the approval, Dr. John Jenkins, director of the FDA's Office of New Drugs, said that ambrisentan “is similar to an existing drug, but offers the potential for fewer drug interactions.”
The FDA based its approval on findings from two studies of almost 400 patients that found treatment significantly increased physical activity capacity and delayed progression of the disease.
This is the sixth drug approved by the FDA for treating PAH; the others are epoprostenol, treprostinil, iloprost, bosentan, and sildenafil, which have all been approved over the last decade. Another endothelin receptor antagonist, sitaxsentan, is approved in Europe, Canada, and Australia, and has been under FDA review.
Over the last decade, the treatment options for PAH have expanded from a treatment that is administered in an intravenous infusion—epoprostenol—to treatments that include oral and inhaled medications, with wide use of combination therapy, because not all patients respond to monotherapy, said Dr. Lewis J. Rubin, professor of medicine at the University of California, San Diego.
The approved indication for ambrisentan is for treatment of PAH (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. Ambrisentan is being marketed under the trade name Letairis by Gilead Sciences Inc., which acquired Myogen Inc., the developer of the drug, in 2006.
The recommended dosage regimen is to start at 5 mg once a day, and if tolerated, to consider increasing the dosage to 10 mg once a day. Because it is teratogenic and has a potential risk of liver toxicity, the drug is available only through a restricted distribution program, the Letairis Education and Access Program (LEAP). Health care professionals, pharmacists, and patients must enroll in this program before they can prescribe, dispense, or receive the drug.
In an interview, Dr. Rubin said bosentan (Tracleer), the endothelin receptor antagonist approved for PAH in 2001, can interact with sildenafil, increasing the metabolism of sildenafil and reducing the metabolism of bosentan. (Sildenafil, marketed as Viagra for erectile dysfunction, is marketed as Revatio for PAH.) The two can be taken together, but optimal dosing is “challenging,” he said.
Ambrisentan is taken once a day, compared with twice a day for bosentan, and the incidence of liver function abnormalities—the major potential toxicity of the endothelin receptor antagonist class—appears to be lower with ambrisentan based on available data, Dr. Rubin said. He added, however, that bosentan has been available longer, so there are more long-term data on the drug. Both appear to be equally efficacious, he said.
Dr. Rubin was the principal investigator of the ARIES-1 and ARIES-2 trials, which “demonstrated that ambrisentan is effective in a number of parameters of disease severity in patients with pulmonary hypertension and that it is a safe drug,” he said. He also served as a consultant to Gilead in the development of the drug.
In the 12-week studies, 393 people with PAH received either placebo or ambrisentan added to current treatment (which could not include any of the drugs approved for PAH).
Compared with placebo, those on ambrisentan had significant improvements in the primary end point, the 6-minute walk distance, at 12 weeks. There was also a significant delay among those on ambrisentan in the time to clinical worsening of PAH.
The most common side effects associated with the drug were peripheral edema, a known class effect of endothelin receptor antagonists, which was usually mild to moderate; nasal congestion; sinusitis; and flushing, according to the FDA. The rate of treatment discontinuations because of side effects was similar (about 2%) for those on placebo and the drug.
Monthly liver function testing is necessary during treatment with ambrisentan. This is a pregnancy category X drug.