Gilead Sciences announced detailed results from the AMBITION study, a Phase 3/4 trial of first-line combination therapy with Letairis (ambrisentan) and tadalafil in patients with WHO/NYHA functional class II and III pulmonary arterial hypertension (PAH).

AMBITION (AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION), conducted in collaboration with GlaxoSmithKline (GSK), was a multicenter, randomized, double-blind, Phase 3/4 study designed to compare the safety and efficacy of investigational first-line combination therapy (Letairis and tadalafil) to first-line monotherapy (Letairis or tadalafil) in patients with WHO/NYHA functional class II and III PAH. The primary endpoint was time to first clinical failure event, a composite endpoint that incorporates both the traditional components of clinical worsening (death, hospitalization and disease worsening) with a component of unsatisfactory long-term clinical response.

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Results of the study showed that combination therapy with Letairis and tadalafil reduced the risk of clinical failure by 50% compared to the pooled Letairis and tadalafil monotherapy arm (HR= 0.50; 95% CI: 0.35, 0.72; P<0.001). The treatment effect for the composite primary endpoint of time to clinical failure was driven mainly by a reduced number of hospitalizations due to PAH, with a reduced risk of hospitalization due to PAH of 63% (HR=0.37; 95% CI: 0.22, 0.64; P<0.001). Consistently favorable reductions in clinical failure events were observed based on etiology, WHO functional class, age, geographical area and gender. The predefined subgroup analysis of the primary endpoint suggested that patients with WHO functional class II (n=155; HR=0.21; 95% CI: 0.07, 0.63); P=0.005) responded even more positively than patients with WHO functional class III (n=345; HR=0.58; 95% CI: 0.39, 0.86; P=0.006). Detailed results were published in The New England Journal of Medicine.

Letairis, a selective endothelin type-A receptor antagonist, and tadalafil, a PDE-5 inhibitor, are each approved as once-daily treatments for patients with PAH (WHO Group 1) with WHO/NYHA functional class II and III symptoms. Combination use is currently not approved.

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