Results From the AMBITION Study of First-Line Treatment With Letairis and Tadalafil in Pulmonary Arterial Hypertension Published in The New England Journal of Medicine

Gilead Sciences, Inc.

today announced detailed results from the AMBITION study (a randomized, double-blind, multicenter study of first-line combination therapy with AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION). In AMBITION, conducted in collaboration with GlaxoSmithKline (GSK), combination therapy with Letairis® (ambrisentan) and tadalafil reduced the risk of clinical failure by 50 percent compared to the pooled Letairis and tadalafil monotherapy arm (hazard ratio = 0.50; 95 percent CI: 0.35, 0.72; p<0.001). These data were published in The New England Journal of Medicine. Letairis, a selective endothelin type-A receptor antagonist, and tadalafil, a PDE5 inhibitor, are each approved in the United States (U.S.), the European Union (EU) and other countries as once-daily treatments for patients with pulmonary arterial hypertension (PAH) (WHO Group 1) with WHO/NYHA functional class II and III symptoms. Letairis is indicated in the U.S. to improve exercise ability and delay clinical worsening and in the EU under the tradename Volibris® to improve exercise capacity. Tadalafil 40 mg is indicated in the U.S. and the EU to improve exercise ability and capacity, respectively. Preclinical data have suggested these therapies may have synergistic effects. However, combination use with Letairis and tadalafil is currently not 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 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. In the primary study analysis, 500 patients were randomized (2:1:1) 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 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 (all events adjudicated by an independent, blinded committee). 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 percent (hazard ratio = 0.37; 95 percent 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; hazard ratio = 0.21; 95 percent CI: 0.07, 0.63); p=0.005) responded even more positively than patients with WHO functional class III (n=345; hazard ratio = 0.58; 95 percent CI: 0.39, 0.86; p=0.006). Statistically significant improvements were also observed with the following secondary endpoints versus the pooled monotherapy arm: change from baseline at week 24 in N-terminal pro-B-type natriuretic peptide (NT-proBNP) (-67 percent vs. -50 percent; p<0.001), percentage of patients with satisfactory clinical response at week 24 (39 percent vs. 29 percent; odds ratio 1.56; p=0.03) and median change from baseline to week 24 in six-minute walk distance (6MWD) (49 meters vs. 24 meters; p<0.001). There was no difference between treatment groups in the change from baseline to week 24 for WHO functional class. No new safety signals were detected with the combination of Letairis and tadalafil. Adverse events occurring more frequently in the combination arm than in either monotherapy arm were peripheral edema (Combination: 45 percent; Letairis: 33 percent; tadalafil: 28 percent), headache (Combination: 42 percent; Letairis: 33 percent; tadalafil: 35 percent), nasal congestion (Combination: 21 percent; Letairis: 15 percent; tadalafil: 12 percent) and anemia (Combination: 15 percent; Letairis: 6 percent; tadalafil: 12 percent). Additional results from the study are available at www.nejm.org. Gilead submitted the AMBITION data in a Letairis supplemental new drug application (sNDA) to the U.S. Food and Drug Administration (FDA) on December 5, 2014. FDA has granted a standard review and set a target review date under the Prescription Drug User Fee Act (PDUFA) of October 5, 2015. In the U.S., Letairis has a labeled BOXED WARNING and an associated Risk Evaluation and Mitigation Strategy (REMS) program regarding the risk of embryo-fetal toxicity; see below for Important U.S. Safety Information for Letairis.