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GSK announces NEJM publication of Phase 3b/4 study of ambrisentan and tadalafil as first-line combination treatment in patients with pulmonary arterial hypertension

Issued: London, UK

GSK today announced publication of the AMBITION study, the first outcomes study to compare the safety and efficacy of investigational first-line combination therapy of Volibris® (ambrisentan) and Adcirca® (tadalafil) to first-line monotherapy of either treatment alone in treatment-naïve patients with pulmonary arterial hypertension (PAH).

The AMBITION study was a randomised, double-blind Phase 3b/4 study designed to compare the efficacy and safety of ambrisentan in combination with tadalafil to monotherapy 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 AMBITION study was co-sponsored by GSK and Gilead. Eli Lilly and Company also provided funding and tadalafil drug supply for the study. 

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). Results of the AMBITION study were first presented at the European Respiratory Society congress in September 2014.

Dr Murray Stewart, Chief Medical Officer, GSK, said: “Combination therapy is commonly used by physicians to treat patients with pulmonary arterial hypertension, but prospective trials of combination therapy have been few in number and limited to sequential add-on therapy, resulting in a lack of evidence about when and how combination treatment could and should be used. Despite existing treatments, the median survival for a PAH patient is just 5-6 years after diagnosis, so the AMBITION study was designed to answer the important question of whether the upfront initiation of treatments with different modes of action could improve patient outcomes in this rare condition. The results of the study significantly advance the body of evidence and understanding in this important area.”

Results of the study are available at www.nejm.org/doi/full/10.1056/NEJMoa1413687.

Regulatory submissions to include the AMBITION data in the Volibris® label are ongoing and planned in the European Union, United States and other countries.

About Ambrisentan and Tadalafil

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. 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.

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.

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.

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 (Volibris®)

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.

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