Rare Disease Report

Combination Therapy (Letairis + Adcirca) for PAH Meets Primary Endpoint in Phase 3b/4 Study

SEPTEMBER 08, 2014
James Radke

Good news for patients with pulmonary arterial hypertension (PAH) – combining therapies of two therapies approved for PAH, Letairis (ambrisentan) with Adcirca (tadalafil) - has a synergistic effect.

Gilead Sciences and GSK announced data from a phase IIIb/IV study to investigate combination therapy of ambrisentan and tadalafil in treatment naïve patients with PAH met the primary endpoint (time to first clinical failure event) by showing superiority of the combination therapy compared to monotherapy treatment (ambrisentan or tadalafil).

Gilead and GSK market Letairis (ambrisentan) in the U.S. and Europe & elsewhere respectively. Eli Lilly markets Adcirca (tadalafil). Both drugs are approved to treat patients with PAH to improve exercise capacity.

The ‘AMBITION’ study was a randomized, double-blind phase IIIb/IV clinical 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 treatment-naïve patients with WHO/NYHA functional class II and III PAH.  Five hundred patients were randomized (2:1:1) to receive ambrisentan and tadalafil combination (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 study found that the combination of ambrisentan 10 mg and tadalafil 40 mg reduced the risk of clinical failure by 50% compared to pooled ambrisentan and tadalafil monotherapy arm (hazard ratio = 0.502; p=0.0002). The combination was also statistically significant versus the individual ambrisentan and tadalafil monotherapy groups for the primary endpoint. 

Statistically significant improvements were also observed for three of the secondary endpoints (6 minute walk distance test, percentage of patients with satisfactory clinical response, change from baseline in N- No new safety signals were detected with the combination of ambrisentan and tadalafil than have been observed with either medicine alone. 

Adverse events observed more frequently in the combination arm than in each monotherapy arm were peripheral oedema (combination: 46%; ambrisentan: 33%; tadalafil: 28%), headache (combination: 42%; ambrisentan: 33%; tadalafil: 35%), nasal congestion (combination: 21%; ambrisentan: 15 %; tadalafil: 12 %) and anaemia (combination: 15%; ambrisentan: 6%; tadalafil: 12%).

Detailed results from the study (Abstract #2916) were presented during an oral session at the annual meeting of the European Respiratory Society (ERS) on September 8, 2014.

Nazzareno Galiè, MD, Professor of Cardiology and Head of the Pulmonary Hypertension Centre, University of Bologna, Italy; Principal Investigator and Co-Chair of the AMBITION Steering Committee said, “The data provided by the AMBITION study represent one of the most important steps forward in the treatment of patients with PAH” adding, “The 50% risk reduction for clinical failure achieved with upfront combination therapy as compared to upfront monotherapy, indicates that this combination treatment strategy could potentially become the standard of care in treatment naïve PAH patients with WHO/NYHA functional class II and III symptoms.”

Lewis J. Rubin, MD, Emeritus Professor, University of California, San Diego and Co-Chair of the AMBITION Steering Committee  said, “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,” adding,  “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.”

The combination use of ambrisentan and tadalafil is not approved anywhere in the world. The companies plan to seek approval for this combination indication by submitting the data from the AMBITION study to regulators in the United States (US), European Union (EU) and the rest of the world.

About Pulmonary Arterial Hypertension

PAH is a rare disease characterized by increased pulmonary-artery pressure in the absence of common causes of pulmonary hypertension, such as chronic heart, lung, or thromboembolic disease.  

At present there is no cure for PAH and the medications currently available are mostly designed to improve blood flow in the lungs.  According to the American Lung Association, approximately 50% of people with PAH die within 5 years of diagnosis. If not treated, average survival is only about 3 years. 

For more information about PAH, visit the Pulmonary Hypertension Association, The American Lung Association, or the National Heart, Lung and Blood Institute

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