GSK announces first-line combination of ambrisentan and tadalafil reduces risk of clinical failure compared to monotherapy in pulmonary arterial hypertension outcomes study

Issued: London, UK

• AMBITION study of ambrisentan/tadalafil combination therapy versus monotherapy achieves primary endpoint of time to first clinical failure event
• Data presented at the ERS International Congress 2014

GSK today 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 today 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.

About Pulmonary Arterial Hypertension (WHO Group 1)

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.

About the AMBITION study

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%).

About Ambrisentan and Tadalafil

GSK commercialises ambrisentan under the tradename Volibris^® in territories outside of the United States and Gilead commercialises ambrisentan under the tradename Letairis^® in the U.S.  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.

For the approved indications and EU summaries of product characteristics for ambrisentan and tadalafil, please visit www.ema.europa.eu.

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.

Important Safety Information for ambrisentan and tadalafil in the European Union

The following Important Safety Information is based on a summary of the Summary of Product Characteristics for both ambrisentan and tadalafil. Please consult the full Summary of Product Characteristics for all the labelled safety information for ambrisentan and tadalafil.

Ambrisentan

Ambrisentan is contraindicated in patients with hypersensitivity to the active substance, to soya or any of the excipients

Ambrisentan is contraindicated in pregnancy. Animal studies have shown that ambrisentan is teratogenic. There is no experience in humans. Women receiving ambrisentan must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs. It is not known whether ambrisentan is excreted in human breast milk. The excretion of ambrisentan in milk has not been studied in animals. Therefore breast-feeding is contraindicated in patients taking ambrisentan

In males, the development of testicular tubular atrophy in male animals has been linked to the chronic administration of endothelin receptor antagonists (ERAs), including ambrisentan.

Ambrisentan has not been studied in a sufficient number of patients to establish the benefit/risk balance in WHO functional class I PAH.

Liver function abnormalities have been associated with PAH. Cases consistent with autoimmune hepatitis, including possible exacerbation of underlying autoimmune hepatitis, hepatic injury and hepatic enzyme elevations potentially related to therapy have been observed with ambrisentan. Therefore hepatic aminotransferases (ALT and AST) should be evaluated prior to initiation of ambrisentan and treatment should not be initiated in patients with baseline values of ALT and/or AST>3xULN.

Peripheral oedema, fluid retention and headache (including sinus headache, migraine) were the most common adverse reactions observed with ambrisentan.

Tadalafil

Tadalafil is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.

Tadalafil is contraindicated in patients that have experienced acute myocardial infarction within the last 90 days and in patients that have severe hypotension (<90/50 mm Hg).

In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated.

Tadalafil is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. Visual defects and cases of NAION have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, to consult a physician immediately. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical studies, and use in these patients is not recommended.

The following groups of patients with cardiovascular disease were not included in PAH clinical studies:

• Patients with clinically significant aortic and mitral valve disease
• Patients with pericardial constriction
• Patients with restrictive or congestive cardiomyopathy
• Patients with significant left ventricular dysfunction
• Patients with life-threatening arrhythmias
• Patients with symptomatic coronary artery disease
• Patients with uncontrolled hypertension.

Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not recommended.

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment.

Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of tadalafil is not recommended.

For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is not recommended. For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the use of tadalafil is not recommended.

The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be informed not to take tadalafil with these medicinal products.

The efficacy and safety of tadalafil co-administered with prostacyclin or its analogues has not been studied in controlled clinical studies. Therefore, caution is recommended in case of co-administration.

The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated.

Tadalafil contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

The most commonly reported adverse reactions, occurring in ≥ 10% of patients in the tadalafil 40-mg treatment arm, were headache, nausea, back pain, dyspepsia, flushing, myalgia, nasopharingitis and pain in extremity. The adverse reactions reported were transient, and generally mild or moderate. Adverse reaction data are limited in patients over 75 years of age.

GSK – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.  For further information please visit www.gsk.com.

Cautionary statement regarding forward-looking statements

GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D 'Risk factors' in the company's Annual Report on Form 20-F for 2013.