When Gilead Sciences, Inc. initiated a clinical trial for first-line combination therapy for pulmonary arterial hypertension treatment, the company felt that their ambitious approach to developing a new, viable therapy for the disease was worthy of the clinical trial name “AMBITION.” Now, according to a news release from Gilead, the company is announcing positive results of the AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION phase 3 clinical trial. The primary endpoint of time to first clinical failure event was reached, with the treatment group experiencing a 50% reduction in risk for an event.
“The pulmonary hypertension medical community has long been interested in determining whether newly diagnosed pulmonary arterial hypertension patients would have improved outcomes with upfront combination therapy versus monotherapy,” said Lewis J. Rubin, MD, co-chair of the AMBITION Steering Committee.
The combined treatment of ambrisentan (Letairis® from Gilead and Volibris® from GlaxoSmithKline) and tadalafil (Adcirca® from Lung Biotechnology, licensed by Eli Lilly Co.) was a first-line treatment for enrolled patients. A dose of 10 mg ambristentan and 40 mg tadalafil was evaluated against monotherapy of either drug. All 500 patients were within WHO/NYHA functional class II and III. They were followed for hospitalization due to worsening pulmonary arterial hypertension, disease progression, dissatisfaction in clinical response, and death.
The combination was powerful enough to reduce the odds ratio for clinical failure to 0.502, which was significant against either monotherapy treatment group. The hazard ratio for time to first hospitalization was 0.372, indicating a 63% lower risk of hospitalization for combination patients. Similar among groups was the rate of serious adverse events. Adverse events varied from peripheral edema to anemia at rates of 45% and 15%, respectively, for the combination group. Greater results disclosure will be available upon a talk delivered at ERS International Congress 2014, occurring September 6-10 in Munich, Germany.
Results contrast what may have been expected due to previous trials evaluating combination therapy for pulmonary hypertension patients, making this study unique. “The majority of combination studies to date have evaluated add-on combination treatment with mixed results,” stated Dr. Rubin.
Gilead worked alongside GlaxoSmithKline in the randomized, double-blind, multicenter study. There are now plans to submit a supplemental new drug application to the Food and Drug Administration by the end of the year to approve combined ambrisentan and tadalafil treatment, although each monotherapy is already approved in the United States and European Union to treat pulmonary arterial hypertension patients in WHO Group 1. “[H]aving demonstrated a 50% 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 pulmonary arterial hypertension,” said Dr. Rubin.