Gilead Sciences Inc. 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 GlaxoSmithKline (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) were presented during an oral session at ERS International Congress 2014, the annual meeting of the European Respiratory Society.
Gilead plans to submit the AMBITION data in a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration by the end of this year. Combination use with ambrisentan and tadalafil is currently not approved.
Ambrisentan, a selective endothelin type-A receptor antagonist, and tadalafil, a PDE5 inhibitor, 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.
“The pulmonary hypertension medical community has long been interested in determining whether newly diagnosed PAH patients would have improved outcomes with upfront combination therapy versus monotherapy,” said Lewis Rubin, emeritus professor, University of California, San Diego and co-chair of the AMBITION Steering Committee. “The majority of combination studies to date have evaluated add-on combination treatment approaches with mixed results. Thus, having demonstrated a 50 percent reduction in risk of clinical failure, the AMBITION results using ambrisentan and tadalafil together as upfront combination therapy potentially establish a new treatment paradigm in PAH.”
AMBITION was a randomized, double-blind study designed to compare the safety and efficacy of investigational first-line combination therapy (ambrisentan and tadalafil) to first-line monotherapy (ambrisentan or tadalafil) in patients with WHO/NYHA functional class II and III PAH. 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 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).
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.
“The AMBITION study is a reflection of Gilead’s ongoing commitment to PAH,” said Norbert Bischofberger, Gilead’s executive vice president of research and development and chief scientific officer. “We are pleased that the combination of ambrisentan and tadalafil has resulted in a clinically meaningful benefit for PAH patients, and we extend our thanks to the patients, investigators and other research collaborators who participated in the study.”
In the United States, 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.
Date: September 8, 2014