Gilead Sciences, Inc., a research-based biopharmaceutical company that discovers, develops and commercializes innovative medicines in areas of unmet medical needs, recently announced detailed data from its AMBITION randomized, double-blind, multicenter study clinical trial assessing its first-line combination therapy with AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertension (PAH).

The trial was conducted in partnership with GlaxoSmithKline (GSK), and the results showed that the combined regimen of Letairis^® (ambrisentan) with tadalafil was able to reduce the risk of clinical failure by 50 percent in comparision to the pooled Letairis and tadalafil monotherapy arm. Results from the AMBITION study were recently published in The New England Journal of Medicine.

Both Letairis, a selective endothelin type-A receptor antagonist that prevents thickening of the blood vessels, especially those in the lungs and heart, and tadalafil, a reversible phosphodiesterase type 5 inhibitor, are approved in the European Union and in the United States as monotherapies for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) with WHO/NYHA functional class II and III symptoms. However, the combined treatment with Letairis and tadalafil is not yet approved.

“The only other published, large-scale, event-driven study to date in PAH compared an endothelin receptor antagonist to placebo in patients who were either treatment-naïve or on background therapy, however, all patients in AMBITION received an approved therapy for PAH,” said Lewis J. Rubin, MD, Emeritus Professor, University of California, San Diego and Co-Chair of the AMBITION Steering Committee. “Thus, the magnitude of the effect with this combination in comparison to active monotherapy is impressive, particularly in WHO functional class II patients where we observed nearly an 80 percent reduction in risk of clinical failure versus monotherapy.”

AMBITION was a Phase 3/4 clinical trial that compared the efficacy and the safety of the combined treatment in patients with WHO/NYHA functional class II and III PAH.

A total of 500 PAH patients were randomized in the first analysis to receive Letairis and tadalafil (n=253) or monotherapy with Letairis (n=126) or tadalafil (n=121) (titrated from 5 mg to 10 mg once-daily and from 20 mg to 40 mg once-daily for Letairis and tadalafil, respectively). The study’s primary outcome was the time to first clinical failure event. This included both the standard components of clinical worsening (disease worsening, hospitalization and death) with a component of unsatisfactory long-term clinical response.

Regarding the primary endpoint of time to clinical failure, the results showed that this was mainly driven by a reduction in the number of hospitalizations due to PAH, with a reduction in the risk of hospitalization due to PAH of 63%.

At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro–brain natriuretic peptide levels than did the pooled-monotherapy group, as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P=0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia.

There were no major safety concerns with the combination the use of the combined treatment.

The occurrence of adverse events were found to be more frequent in the combined treatment study arm compared to either the monotherapy arm. They included peripheral edema (Combined treatment: 45%; Letairis: 33%; tadalafil: 28%), headache (Combined treatment: 42%; Letairis: 33%; tadalafil: 35%), nasal congestion (Combined treatment: 21%; Letairis: 15%; tadalafil: 12%) and anemia (Combined treatment: 15%; Letairis: 6%; tadalafil: 12%).

According to the researchers, the AMBITION study found that among PAH patients who had not received previous treatment, the risk of the composite outcome of clinical failure was significantly lower among those who received initial combination therapy with ambrisentan and tadalafil than among those who received monotherapy with either ambrisentan or tadalafil.