Date: 2015-08-26
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in The New English Journal of Medicine
Company: Gilead (USA - CA) GSK (UK)
Product: combination of ambrisentan and tadalafil
Action
mechanism: endothelin receptor antagonist/phosphodiesterase type 5 inhibitor. Ambrisentan (Leitaris®/Volibris®) is a selective endothelin type-A receptor antagonist, and tadalafil, a PDE5 inhibitor. They are each approved in the United States, the European Union (EU) and other countries as once-daily treatments for PAH (WHO Group 1), in patients with WHO/NYHA functional class II and III symptoms. Ambrisentan is indicated in the U.S. to improve exercise ability and delay clinical worsening and in the EU 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. 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 Letairis Important Safety Information.
Disease: pulmonary arterial hypertension (PAH)
Therapeutic area: Rare diseases - Cardiovascular diseases
Country: Australia, Austria, Belgium, Canada, France, Germany, Greece, Italy, Japan, The Netherlands, Spain, Sweden, UK, USA
Trial
details: AMBITION was a randomized, double-blind study designed to compare the safety and efficacy of two treatment strategies; first-line combination therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil) in patients with WHO/NYHA functional class II and III pulmonary arterial hypertension. In the study, 500 patients were randomized (2:1:1) to receive ambrisentan and tadalafil (n=253) or monotherapy with ambrisentan (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 ambrisentan and tadalafil, respectively). The primary endpoint was time to first clinical failure event, defined as time from randomization to the first occurrence of death (all-cause), hospitalization for worsening PAH, disease progression or unsatisfactory long-term clinical response (events adjudicated by an independent, blinded committee).The purpose of this study is to compare the two treatment strategies; first-line combination therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil) in subjects with pulmonary arterial hypertension. This will be assessed by time to the first clinical failure event. (NCT01178073) The AMBITION study was cosponsored by Gilead and GSK. Eli Lilly and Company also provided funding and tadalafil drug supply for the trial. Gilead commercializes ambrisentan under the tradename Letairis® in the U.S. and GSK commercializes ambrisentan under the tradename Volibris® in territories outside of the United States.
Latest
news: * On August 26, 2015, Gilead Sciences 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 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. * On September 8, 2014, Gilead Sciences announced 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), which was conducted in collaboration with GSK. In AMBITION, first-line treatment of pulmonary arterial hypertension (PAH) with the combination of ambrisentan 10 mg and tadalafil 40 mg reduced the risk of clinical failure by 50 percent compared to the pooled ambrisentan and tadalafil monotherapy arm (hazard ratio = 0.502; 95 percent CI: 0.348, 0.724; p=0.0002). The combination was also statistically significant versus the individual ambrisentan and tadalafil monotherapy groups for the primary endpoint (p<0.01). Rates of serious adverse events and events leading to discontinuation were similar across treatment arms. Detailed results from the study (Abstract #2916) will be presented during an oral session at ERS International Congress 2014, the annual meeting of the European Respiratory Society. The treatment effect observed with the primary endpoint was mainly driven by a reduction in hospitalizations. Time to first hospitalization was reduced by 63 percent (hazard ratio = 0.372; 95 percent CI: 0.217, 0.639; p=0.0002). 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) (-67.4 percent vs. -49.7 percent; p<0.0001), percentage of patients with satisfactory clinical response at week 24 (39 percent vs. 29 percent; p=0.026) and median change from baseline to week 24 in six-minute walk distance (6MWD) (49.0 meters vs. 23.8 meters; p<0.0001). 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 ambrisentan and tadalafil. Adverse events occurring more frequently in the combination arm than in each monotherapy arm were peripheral edema (Combination: 45 percent; ambrisentan: 33 percent; tadalafil: 28 percent), headache (Combination: 42 percent; ambrisentan: 33 percent; tadalafil: 35 percent), nasal congestion (Combination: 21 percent; ambrisentan: 15 percent; tadalafil: 12 percent) and anemia (Combination: 15 percent; ambrisentan: 6 percent; tadalafil: 12 percent). Gilead plans to submit the AMBITION data in a supplemental new drug application (sNDA) to the FDA by the end of this year. Combination use with ambrisentan and tadalafil is currently not approved.
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. 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).
Gilead submitted the AMBITION data in a Letairis supplemental new drug application (sNDA) to the 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.
