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GSK announced that the first phase IIIb/IV study, conducted in collaboration with Gilead Sciences Inc., to investigate combination therapy of ambrisentan and tadalafil in treatment naïve patients with pulmonary arterial hypertension (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). The length of time before patients experienced clinical failure was significantly prolonged for those receiving first-line combination compared to monotherapy.
The randomised, double-blind, multicentre, ‘AMBITION’ study showed that first-line treatment of PAH with the combination of ambrisentan 10 mg and tadalafil 40 mg reduced the risk of clinical failure by fifty percent (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-terminal pro-B-type natriuretic peptide). The remaining two secondary endpoints (WHO functional class and Borg dyspnea index) did not meet statistical significance. 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 the annual meeting of the European Respiratory Society (ERS).
“The data provided by the AMBITION study represent one of the most important steps forward in the treatment of patients with PAH” said 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. “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.”
The companies now 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.
“As part of our efforts to further help patients who suffer with this rare and debilitating lung disease, GSK and Gilead took a major step to jointly sponsor the first study to investigate whether there was an advantage to use upfront combination of ambrisentan and tadalafil compared to first-line monotherapy with either medicine” said Dr. Carlo Russo, senior vice president, head of GSK Rare Diseases Research & Development. “We thank all the investigators, study teams and especially the patients for diligently participating in this study that lasted for 3.5 years and we now look forward to submitting an application to regulatory authorities in the coming months.”
The combination use of ambrisentan and tadalafil is not approved anywhere in the world. Preclinical data suggested these therapies may have synergistic effects.
Ambrisentan, a selective endothelin type-A receptor antagonist, and tadalafil, a PDE-5 inhibitor, are each approved in the EU and other countries as once-daily treatments for PAH, (WHO Group 1) in patients with WHO/NYHA functional class II and III symptoms. In the EU, ambrisentan is indicated for the treatment of adult patients with PAH classified as WHO functional class II and III, to improve exercise capacity. Tadalafil is indicated in adults for the treatment of PAH classified as WHO functional class II and III, to improve exercise capacity.
PAH is a debilitating disease characterised by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. PAH afflicts approximately 200,000 patients worldwide.
The AMBITION study was co-sponsored by GSK and Gilead. Eli Lilly and Company also provided funding and tadalafil drug supply for the trial.
AMBITION was a randomised, double-blind phase IIIb/IV 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. In the study, 500 patients were randomised (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 randomisation to the first occurrence of death (all-cause), hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response (events adjudicated by an independent, blinded committee).
Analysis of the time to first individual component of clinical failure indicates the treatment effect observed was primarily driven by a reduction in hospitalisations.
No new safety signals were detected with the combination of ambrisentan and tadalafil than have been observed with either medicine alone. Adverse events occurring 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%).
GSK commercialises ambrisentan under the tradename Volibris in territories outside of the United States and Gilead commercialises ambrisentan under the tradename Letairis in the US. Ambrisentan has been granted orphan drug status for the treatment of PAH in Australia, Europe, Japan, Korea and United States. GSK also has an exclusive license from Eli Lilly and Company to promote tadalafil for PAH under the tradename Adcirca in Europe.
Letairis and Volibris are registered trademarks of Gilead Sciences, Inc or one of its related companies. Adcirca is a registered trademark of Eli Lilly and Company.
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